
==== Front
Cell Biol Toxicol
Cell Biol Toxicol
Cell Biology and Toxicology
0742-2091
1573-6822
Springer Netherlands Dordrecht

39276283
9919
10.1007/s10565-024-09919-9
Review
tRNA modifications and tRNA-derived small RNAs: new insights of tRNA in human disease
Wu Di 1
Li Xiuling 2
Khan Faheem Ahmed 3
Yuan Chenyang 4
Pandupuspitasari Nuruliarizki Shinta 5
Huang Chunjie goodlife.huang@ntu.edu.cn

1
Sun Fei sunfeisrrsh@zju.edu.cn

1
Guan Kaifeng guankaifeng1121@pku.edu.cn

6
1 https://ror.org/02afcvw97 grid.260483.b 0000 0000 9530 8833 Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001 China
2 https://ror.org/04eq83d71 grid.108266.b 0000 0004 1803 0494 College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, 450046 China
3 https://ror.org/02hmjzt55 Research Center for Animal Husbandry, National Research and Innovation Agency, Jakarta Pusat, 10340 Indonesia
4 https://ror.org/0051rme32 grid.144022.1 0000 0004 1760 4150 College of Veterinary Medicine, Northwest A&F University, Yangling, 712100 China
5 https://ror.org/056bjta22 grid.412032.6 0000 0001 0744 0787 Faculty of Animal and Agricultural Sciences, Universitas Diponegoro, Semarang, 1269 Indonesia
6 https://ror.org/02v51f717 grid.11135.37 0000 0001 2256 9319 School of Advanced Agricultural Sciences, Peking University, Beijing, 100871 China
14 9 2024
14 9 2024
2024
40 1 7610 6 2024
4 9 2024
© The Author(s) 2024
2024
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tRNAs are codon decoders that convert the transcriptome into the proteome. The field of tRNA research is excited by the increasing discovery of specific tRNA modifications that are installed at specific, evolutionarily conserved positions by a set of specialized tRNA-modifying enzymes and the biogenesis of tRNA-derived regulatory fragments (tsRNAs) which exhibit copious activities through multiple mechanisms. Dysregulation of tRNA modification usually has pathological consequences, a phenomenon referred to as "tRNA modopathy". Current evidence suggests that certain tRNA-modifying enzymes and tsRNAs may serve as promising diagnostic biomarkers and therapeutic targets, particularly for chemoresistant cancers. In this review, we discuss the latest discoveries that elucidate the molecular mechanisms underlying the functions of clinically relevant tRNA modifications and tsRNAs, with a focus on malignancies. We also discuss the therapeutic potential of tRNA/tsRNA-based therapies, aiming to provide insights for the development of innovative therapeutic strategies. Further efforts to unravel the complexities inherent in tRNA biology hold the promise of yielding better biomarkers for the diagnosis and prognosis of diseases, thereby advancing the development of precision medicine for health improvement.

Keywords

tRNA modification
tRNA-modifying enzyme
tRNA-derived regulatory fragments
tRNA modopathy
Chemoresistance
Natural Science Foundation of the Higher Education Institutions of Jiangsu Province22KJB180006 Wu Di http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82371613 32302844 Sun Fei Guan Kaifeng http://dx.doi.org/10.13039/501100012166 National Key Research and Development Program of China 2021YFC2700200 Sun Fei issue-copyright-statement© Springer Nature B.V. 2024
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pmcIntroduction

Since the 1950s, when pseudouridine was identified in RNA molecules (Cohn 1951), RNA modification has been known recognized as a conserved phenomenon across all life kingdoms, with important yet enigmatic functions. Transfer RNAs (tRNAs) are a category of small non-coding RNAs with a ‘cloverleaf’ structure composing of four arms and three loops (Fig. 1). Their primary function is to interpret the genetic codes in mRNA by delivering cognate amino acids to the ribosome for protein synthesis (Schimmel 2018). They also act as signaling molecules that interact with other RNAs and proteins (Kuhle et al. 2023). The human genome encodes up to 274 tRNA species from 446 tRNA genes, including 22 mitochondrial (mt-)tRNAs, which have the highest number and most diversity of chemical nucleosides (up to 25% nucleotides per tRNA) (Goodenbour and Pan 2006; Boccaletto et al. 2018) (Fig. 1 and Table 1). tRNA genes decode 61 codons for 20 amino acids (Goodenbour and Pan 2006). Of over 170 RNA modifications, 80% are found in tRNAs, with 18 in mt-tRNAs (Barbieri and Kouzarides 2020; Suzuki et al. 2020; Schöller et al. 2021). These modifications significantly affect tRNA folding, stability, and function (Suzuki 2021).Fig. 1 Biogenesis of tRNA and tRNA-derived fragment (tsRNA), and representative well-known nucleotide modifications in tRNA. Mammalian tRNA is synthesized as pre-tRNA transcript that contains a 3′-trailer, which is cleaved by endonuclease Z (RNase Z) or other exonucleases, a 5′‐leader that is cleaved by RNase P, and introns that are spliced out by tRNA splicing endonuclease complex. During maturation, a 3′ terminal CCA trinucleotide is ligated to the tRNA. The maturation tRNA is then aminoacylated by its cognate aminoacyl-tRNA synthetase and escorted to the ribosome, where it acts as a codon decoder, converting the transcriptome into the proteome. tRNAs are extensively modified with various reversible nucleotide modifications, which are catalyzed by a set of modifying and de-modifying enzymes that are crucial for their folding, stability, and function. Another layer of complexity in tRNA biology is the enigmatic realm of tsRNAs, which have significant implications in health and disease

Table 1 A brief summary of some tRNA modifications and their functions and clinic significance

Modification type	Position	Modifying-enzyme	Molecular function	Clinical significance	
2’-O-methylation (Nm)	C32/G34/U34	Trm7

hTRMT13 (CCDC76)

FTSJ1

	Drives hydroxywybutosine (OHyW) at m1G37 in tRNAphe;

Promotes SAMD9-mediated tRNAphe cleavage

	X-linked intellectual disability (XLID)

Poor prognosis in cancers

	
Queuosinylation (Q)	U34	eTGT	Promotes m5C38;

Maintains expression of tight junction proteins, such as Claudin-2/5

	Inflammatory bowel disease (IBD)	
Cytosine-3-methylation (m3C)	32	METTL2/6

METTL8

	Promotes ribosome occupancy;

Facilitates translation of mitochondrial proteins

	Stem cell differentiation;

Tumor growth and poor patient survival;

Metabolic disorder

	
Cytosine-5-methylation (m5C)	34/38/48/49/50/72	DNMT2

NSUN2

	Protect tRNA from endonucleolytic cleavage;

Promotes translation efficacy

	Neurodevelopmental disorder;

Intergenerational inheritance of paternally acquired traits

	
N1-methyadenosine (m1A)	9/14/58	TRMT6&TRMT61A

TRMT10C

TRMT61B

	Promotes stemness and survival of cancer stem cells;

Drives T cell activation and immune response

	Alzheimer’s disease;

Tumor growth;

Adaptive immunity

	
N7-methyguanosine (m7G)	45/46/47	METTL1&WDR4	Regulates cell cycle;

Activates Wnt/β-catenin & mTOR/Ulk1 signaling

	Cancer progression & Chemoresistance	
Carboxymethyluridine (cm5U)	U34	ELP3	Promotes translation efficiency	Respiratory disease	
Pseudouridylation (Ψ)	8	PUS7	Controls stem cell fate commitment;

Promotes translation of pyrimidine-enriched sequence containing transcripts

	Myelodysplastic syndrome;

Leukaemogenesis and poor patient survival

	

Dysregulation of tRNAs is a risk factor for several human cancers, including breast and prostate cancer (He et al. 2020). Recent research underscores the medical importance of tRNA modifications, as deficiencies in tRNA-modifying enzymes usually incurs pathological consequences, such as malignancies, neurological disorders and mitochondrial diseases, a phenomenon termed ‘tRNA modopathy’ (Ignatova et al. 2020; Chujo and Tomizawa 2021; Orellana et al. 2021; Nagayoshi et al. 2021; Suzuki 2021; Han et al. 2022; Li et al. 2022; Shafik et al. 2022; Zhang et al. 2023a). Deregulated tRNA modifications are closely associated with poor prognosis and chemoresistance in common cancers (Dai et al. 2021; Schöller et al. 2021; Pagano et al. 2022; Wang et al. 2023; Zhao et al. 2024). For example, data from the Cancer Genome Atlas Program show that upregulation of Nol1/Nop2/SUN domain methyltransferase 2 (NSUN2), a tRNA cytosine-5 methylation (m5C) writer, correlates with a shorter patients' survival in nearly all cancer types (Cheng et al. 2023). These findings indicate that dysfunction in tRNA-modifying enzyme is a contributing factor to the etiology of various clinically relevant diseases.

tRNA-derived small RNAs (tsRNAs) are emerging as significant players in tRNA biology. These conserved functional fragments are site-specifically cleaved from tRNAs by stress-activated ribonucleases and regulate various biological events via mechanisms such as acting as miRNA-like molecules (Fig. 1) (Berg and Brandl 2021; Fu et al. 2023). The biogenesis and activity of tsRNAs are influenced by tRNA modifications, and their deregulation is also linked to several human diseases and the resistance to cancer chemotherapy (Balatti et al. 2017; Zhang et al. 2019; Yu et al. 2020; Orellana et al. 2021; Guzzi et al. 2022; van Ingen et al. 2022; García-Vílchez et al. 2023a, b). Thus, not only being potential diagnostic biomarkers, tRNA-modifying enzymes and tsRNAs are also promising therapeutic targets for disease treatment, especially for chemoresistant cancers, including triple-negative breast cancer (TNBC) and lung adenocarcinoma.

tRNA and its derivatives are prominent regulatory molecules in the ever-expanding epitranscriptome, yet a full landscape of their biological functions, of their modifying enzymes that install or erase site-specific modifications, and of their binding proteins are still underexplored. Here, we review recent discoveries on several well-studied tRNA modifications, tsRNAs biogenesis and activity, and their implications in human diseases, especially malignancies. We will also discuss the therapeutic potential of tRNA/tsRNA-based therapies, aiming to inform innovative strategies mitigating human disease, despite ongoing challenges.

Molecular structure of some tRNA-modifying enzymes

The overall structure of tRNA-modifying enzymes is highly conserved across species. The functional domains and 3D structures of some tRNA-modifying enzymes are shown in Fig. 2. FtsJ RNA methyltransferase homolog 1 (FTSJ1, ortholog of yeast Trm7) is involved in tRNA 2'-O-methylation (Nm) and is conserved across species. Expression of human FTSJ1 in yeast alleviates the growth defects of Trm7-depleted mutants (Guy and Phizicky 2015). Nol1/Nop2/SUN domain methyltransferase 2 (NSUN2) and DNA methyltransferase 2 (DNMT2, formerly known as TRDMT1) are responsible for tRNA cytosine-5 methylation (m5C). NSUN2 consists of a central catalytic domain that contains the S-adenosyl-L-methionine (SAM) binding site, two RNA recognition motifs (RRMs) that interact with specific RNA sequences, and a nuclear localization signal (NLS) at N-terminus that escorts it to the nucleus. Despite DNMT2 bears sequence motifs which are highly homologous to those of DNA methyltransferases, it does not methylate DNA but instead species-specifically methylates tRNAmolecules with a preference for interacting with their anticodon loop (Jeltsch et al. 2017). It stands as an example of how RNA methyltransferase drives m5C using the DNA methyltransferase-like mechanism, ableit distinct residues are required for the transferring of methyl group by RNA m5C and DNA m5C methyltransferases (Liu and Santi 2000; Jeltsch et al. 2017; Yang et al. 2020). Several residues, including R84, R95, K122, R275, R289, K295, K367, and R371, that are located proxmitity to the binding pocket for SAM are identified to be essential for the catalytic activity of DNMT2. Methyltransferase-like proteins (METTL2, METTL6, and METTL8) are involved in tRNA cytosine-3 methylation (m3C), while METTL1 deposits N7-methylguanosine (m7G) modification on tRNA. They both contain a SAM binding site and a catalytic domain.Fig. 2 Catalytic domains and 3D structures of some tRNA-modifying enzymes in eukaryotes. The structures for each protein are taken from PDB database. The proteins in a ruler is shown upto 1000 amino acids to maintain the uniformity of all protein. The 1–1000 amino acids line is used as a ruler. The different proteins lengths are varied and the ruler of 1–1000 amino acids is kept constant to visualize the size of each protein. The start and end of domains positions can be visualized in the figure. The names in the shapes are the names of the domains present in the particular protein and different colors are given to each domain to easily differentiate from other

Are tRNA-modifying enzymes drugable targets?

Mechanism-based inhibitors that mimic the reactive intermediates in specific reaction pathway are promising candidates for modulating the epitranscriptome. Developing pharmacological inhibitors that specifically target tRNA-modifying enzymes is particularly challenging due, in part, to the highly conserved nature of their active sites. An incomplete understanding of their catalytic mechanisms and structural details also hinders the innovation of therapeutic drugs against these enzymes. Given their medical significance, research in this area is ongoing and is of interest in epitranscriptomics and medicinal chemistry.

An active compound of the extract of mushroom Lepista inversa, 2,6-diamino purine (DAP), which can increase p53 levels in Calu-6 cancer cells, is shown to be a Ftsj1 inhibitor (Trzaska et al. 2020). DAP features low-toxicity, making it a promising therapeutic drug (Trzaska et al. 2020). In another study, three 1,2,4-oxadiazole derivatives (NV848, NV914, and NV930) are also reported with inhibitory activity against Ftsj1 (Carollo et al. 2023).

Some inhibitors targeting DNA methylation, such as zebularine, oligodeoxynucleotides, azacytidine, and decitabine, have been developed for epigenetics-driven therapeutics (Zhou et al. 2002; Schaefer et al. 2010). Azacytidine has been shown to inhibit DNMT2-driven methylation of cytosine 38 in tRNAAsp, and this inhibitory effect may be specific to DNMT2 target sites, as hypomethylation at the sites known to be targeted by other RNA methyltransferases is not observed following azacytidine treatment (Schaefer et al. 2009). The cofactor SAM binding site exhibits favorable druggability, and the small-molecule inhibitors that compete with SAM represent potential therapeutic agents against tRNA methyltransferases (Nai et al. 2023). The derivative of SAM, S-adenosyl-L-homocysteine (SAH), along with the natural product pan-methyltransferase inhibitor sinefungin (SFG), has been identified as Dnmt2 inhibitors (Schwickert et al. 2022; Zimmermann et al. 2023). Through a microscale thermophoresis assay designed for screening DNMT2 inhibitor, several synthetic derivatives of N-adenosyl-2,4-diaminobutyric acid (Dab) have been identified as potential candidates, with the alkyne-substituted derivatives of Dab exhibiting similar inhibitory efficacy to that of SAH and SFG. However, the poor membrane permeability of these acids and the rapid hydrolysis of the ethyl ester prodrug compromise their cellular activities (Schwickert et al. 2022). Very recently, a 4-bromo-3-nitrophenylsulfonamide-decorated SAH derivative turns out to be a potent and selective covalent DNMT2 inhibitor (Schwickert et al. 2023).

Through cysteine-directed activity-based protein profiling, azetidine acrylamides, in particular the 2R, 3S isotype, are discovered as stereoselective covalent inhibitors of human NSUN2. Despite targeting the conserved catalytic cysteine residue (C271) shared by NSun family members (NSun1-7 in humans), those compounds display selective activities against NSUN2 and, by disrupting the NSUN2-tRNA interaction, they induce a global reduction in tRNA m5C marks in cancer cells (Tao et al. 2023). These findings pave the way to develop isotype-selective and cell-active inhibitors of tRNA methyltransferases with covalent chemistry targeting the conserved catalytic cysteine residues (Tao et al. 2023). By leveraging the AI-directed structure activity relationship analysis and functional assay, several small-molecule compounds against NSUN1/2 are identified from the AI-designed drug library. These inhibitors overcome NSUN1/2-induced chemoresistance to venetoclax in acute myeloid leukemia (AML) cell lines and AML mouse model (Cheng et al. 2023). AI algorithms require high-quality training datasets, including validated 3D protein structure and the information on structural flexibility. As such, a deeper understanding of tRNA-modifying enzymes will foster the AI-based development of their inhibitors.

Using in silico screening (high-throughput docking) of a compound library containing 4896 adenine derivatives, eleven compounds which belong to three different chemotypes are identified to show inhibitory activity against METTL1, and two adenine derivatives exhibit very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations suggest that those compounds inhibit METTL1 by competing with SAM for the binding site within METTL1 (Nai et al. 2023).

N1-methyladenosine (m1A) methylation on tRNA can be catalyzed by a methyltransferase complex consisting of an RNA binding subunit TRMT6 and a catalytic subunit TRMT61A, thus blocking TRMT6-TRMT61A interaction therefore holds the potential to suppress TRMT6/TRMT61A-driven tRNA m1A modification. With this purpose in mind, Wang et al. identified 3 compounds (thimerosal, phenylmercuric acetate, and thiram) from a FDA-approved drug bank that potently inhibit TRMT6/TRMT61A-driven tRNA m1A modification. TRMT6/TRMT61A-mediated m1A methylation is significantly increased in advanced hepatocellular carcinoma (HCC) tumors, which is negatively correlated with HCC survival. As expected, thiram exhibits attractive anti-tumourigenic effects in mice bearing HCC patient-derived tumor cells, and, importantly, the landscapes of other RNA modifications including m1G and Ψ are not affected by thiram, indicating that thiram is an efficient inhibitor of TRMT6/TRMT61A.

tRNA modifications and their clinical significance

The anticodon position 34 (‘‘wobble’’ position) is one of the most heavily modified tRNA sites, where the existence of a variety of modifications impact codon-anticodon pairing and translational preference; while modifications of the adjacent position 37 affect decoding and translational fidelity (Suzuki 2021). With known or unknown functional relevance, tRNA modifications have been identified across species (Fig. 1), constituting an important mechanism of epigenetic regulation. Deregulation of tRNA modification usually has pathological outcomes. Some of the well-studied tRNA modifications and the molecular mechanisms underlying tRNA modopathies will be included. Importantly, genetic studies in Saccharomyces cerevisiae suggest a collaboration of specific tRNA modifications in maintaining translational efficiency. The phenotypical alterations induced by defective tRNA modifications can be partially compensated by eEF1A, an elongation factor that delivers tRNA to the ribosome (Klassen and Schaffrath 2018).

Pseudouridine

Among the over 170 types of modified nucleosides identified to date, pseudouridine (Ψ) is the most abundant RNA modification across organisms that modulates RNA structure, metabolism, and interactome. Ψ is catalyzed by group of pseudouridine synthases (PUS), and there are 13 PUSs found in humans, namely PUS1, PUSL1, PUS3, TRUB1, TRUB2, DKC1, PUS7, PUS7L, RPUSD1, RPUSD2, RPUSD3, RPUSD4, and PUS10. It can facilitate translation via either snoRNA-dependent or pseudouridine synthase (PUS)-dependent mechanism (Karijolich et al. 2015; Borchardt et al. 2020).

In principle, Ψ affects almost all aspects of tRNA life cycle, including translation efficacy and tRNA fragmentation. In yeast, PUS3 installs Ψ at U38 and U39 in at least 19 tRNAs, including tRNAGlnUUG, tRNATrpCCA, tRNALeuCAA, which is essential for yeast growth at elevated temperatures (Han et al. 2015). The functional relevance of most endogenous Ψ in human tRNAs remains unknown. PUS10 deficiency has no obvious influence on protein synthesis, albeit inducing a slight change in ribosome occupancy revealed by ribosome profiling, while loss of PUS7 increases protein synthesis via a mechanism involving the biogenesis of a specific subset of tsRNAs which initiate translational reprogramming (Guzzi et al. 2018; Song et al. 2020). Other evidence proposes that pseudouridine may contribute to the cell-type specific fine-tuning of tRNA function, coordinating codon bias to translational adaptation during stress responses (Chan et al. 2018).

2'-O-methylation

2'-O-methylation (Nm), methylation of ribose moiety at 2’-OH group, can occur on any nucleotide and is among the most common RNA modifications in kingdoms of life. Nm on ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs) are typically catalyzed by the evolutionarily conserved C/D-box small RNAs which contain the guide ribonucleoprotein particles involving fibrillarin, with small nucleolar RNPs (snoRNPs) deposit Nm on rRNAs and small Cajal bodies RNPs install Nm on snRNAs (Angelova et al. 2020). Nm deposition also occurs at 3′-terminal nucleotides in mammalian mRNA and PIWI-interacting RNAs (piRNAs) (Kurth and Mochizuki 2009; Ringeard et al. 2019). rRNA posttranscriptional modification is reported to influence translational fidelity by optimizing the function and structure of ribisome (Baxter-Roshek et al. 2007). In eukaryotes, Nm of cytidine at position 32 (C32) and guanosine at position 34 (G34) of tRNAPhe, C32 and C34 of tRNATrp, and uridine at position 34 (U34) of tRNALeu is ‘written’ by human 2′-O-methyltransferase FTSJ1 or its functional ortholog yeast Trm7 (Angelova et al. 2020; Nagayoshi et al. 2021). Importantly, N6-isopentenyladenosine (i6A) and 1-methylguanosine at position 37, i6A37 and m1G37, respectively, are prerequisites for Nm (Guy and Phizicky 2015).

tRNAPhe is the most biologically relevant substrate for FTSJ1 in eukaryotes (Guy and Phizicky 2015). FTSJ1 physically interacts with the anticodon nuclease Sterile Alpha Motif Domain-Containing Protein 9 (SAMD9), and the preexisting FTSJ1-driven Nm34 in tRNAPhe is required for SAMD9-mediated cleavage of tRNAPhe that causes codon-specific ribosomal pausing and protein synthesis inhibition (Zhang et al. 2023b). The nuclease activity of SAMD9 can be activated by virus infection, and the constitutively activated SAMD9 has implications in various human diseases, including myeloid malignancies (Wong et al. 2018; Zhang et al. 2023b). SAMD9 deficiency or tRNAPhe overexpression restores protein synthesis and virus replication (Zhang et al. 2023b), suggesting tRNA 2'-O-methylation is a novel mechanism for antiviral innate immunity. Notably, FTSJ1-driven Nm34 in tRNAPhe also drive the formation of hydroxywybutosine (OHyW) at m1G37 (Li et al. 2020).

FTSJ1 deficiency is linked with some pathological conditions, such as nonsyndromic X-linked intellectual disability (XLID), a neurological disease affecting 2–3% of the population worldwide (Li et al. 2020; Nagayoshi et al. 2021). The intellectual disability associated protein FTSJ1 primarily localizes in cytoplasm and is reported to interact with auxiliary protein WDR6, a homolog of yeast Trm734, to catalyze Nm34 modification. This modification in tRNAPheGAA promotes translation efficiency of the TTT-biased transcripts which have enrichment in regulation of nervous system development (Li et al. 2020). In both FTSJ1-deficient mice and XLID patient-derived cells, FTSJ1-driven tRNA Nm on 11 species of tRNAs is absent (Nagayoshi et al. 2021). Loss of FTSJ1-driven Nm34 decreases the stability of tRNAPhe in the brain and thus reduces the decoding efficiency of a repertoire of genes required for synaptic morphogenesis and synaptic plasticity, leading to anxiety-like and intellectual deficits that recapitulate some phenotypes in XLID patients with FTSJ1 mutation (Nagayoshi et al. 2021). Importantly, beyond intellectual disability, FTSJ1-deficient mice display many other abnormalities, such as, pain sensing, bone and energy metabolism, and immune function (Jensen et al. 2019). FTSJ1 deficiency is also associated with the tumorigenesis of non-small cell lung cancer (NSCLC), the leading cause of cancer mortality worldwide. FTSJ1 overexpression, by down-regulating the DNA damage-regulated autophagy modulator 1 (DRAM1), compromises the proliferation, migration, and survival of NSCLC cells, while its knockdown causes opposite effects (He et al. 2020).

Nm of wobble cytidine (C34) in human elongator tRNAMetCAT requires the collaboration of a nucleolar and a Cajal body (CB)-specific box C/D ribonucleoprotein particles (RNPs) carrying SNORD97 and SCARNA97 C/D box small nucleolar RNA (snoRNA) that guide 2′-O-methylation (Vitali and Kiss 2019), representing an example of RNA-directed tRNA modification. snoRNA, from which the small RNAs are likely to be derived and reflects the intracellular level of a small RNA, these tRNA-related small RNAs are expected to be more abundant than most of the miRNAs. Very recently, the C/D snoRNA AF357425/SNORD113-6 is shown to drive Nm modification in tRNA leucine anti-codon TAA (tRNALeuTAA) and protect its site-specific fragmentation (van Ingen et al. 2022). The abundances of AF357425 and tRNALeuTAA are increased by hypoxic or oxidative stress, and AF357425 knockdown decreases overall biogenesis of tRNA-derived fragments (tsRNAs) but induces an enrichment in smaller tsRNAs (< 30 nucleotides), such as tsRNALeu47-64 (van Ingen et al. 2022), implicating a regulatory circuitry between AF357425 and tRNA stability via 2′-O-methylation.

In addition to FTSJ1, the human TRMT13 (hTRMT13), also known as coiled-coil domain-containing protein 76 (CCDC76), is defined as another methyltransferase for tRNA 2'-O-methylation. hTRMT13 contains a CHHC zinc finger domain that can bind to either DNA or tRNA. Its expression is strongly linked to poor patient survival in various cancers, including breast carcinoma and pancreatic cancer (Li et al. 2022). Nuclear hTRMT13 regulates the transcription of various genes, especially those involved in cell migration, as a transcriptional cofactor; while in the cytoplasm, hTRMT13 catalyzes 2'-O-methylation at position 4 (Nm4) in the acceptor stem of tRNAs to regulate translation program (Li et al. 2022). However, the pro-metastatic activity of hTRMT13 in breast tumor metastatic mice models, presumably by transcriptionally activation of oncogenic TGFB1, PKN2, and MEF2A, is independent of its tRNA-modifying activity (Li et al. 2022). Thus, the functional relevance of hTRMT13-driven tRNA 2'-O-methylation remains to be explored.

Queuosinylation

Queuosinylation is a modification in which guanine at the wobble uridine (U34) position is replaced with queuosine (Q) in G34U35N36 anticodon-containing tRNAs- tRNAAspGUC, tRNAHisGUG, tRNATyrGUA, and tRNAAsnGUU (Zhang et al. 2020a). In eukaryotes, the precursor of Q, queuine, is salvaged from gut microbiota and diet, and incorporation of hypermodified Q into the wobble position of tRNA is driven by the eukaryote tRNA-guanine transglycosylase (eTGT), leading to tRNA queuosinylation (Q-tRNA) (Katze et al. 1982). Q-tRNA is important for translational fidelity and efficiency, and its deficiency is associated with diseases including malignancy (Tuorto et al. 2018; Zhang et al. 2023a). The heterodimeric eTGT consists of a catalytic subunit queuine tRNA-ribosyltransferase 1 (QTRT1) and a noncatalytic partner subunit QTRT2. In patients with inflammatory bowel disease (IBD) and colitis mouse models, a decreased expression of QTRT1 in their intestine is observed, which causes deregulation in Claudin-2/5, two transmembrane barrier proteins, contributing to a leaky tight junction in the inflammatory intestine (Zhang et al. 2023a). Queuine treatment benefits intestinal barrier integrity under colitis and shows protective activity against neurodegeneration (Richard et al. 2021; Zhang et al. 2023a). Queuine depletion triggers the activation of unfolded protein response and endoplasmic reticulum stress, due to translation deregulation, in cultured human cells and germ-free mice (Tuorto et al. 2018). These findings suggest that queuine or queuine-producing probiotics hold the therapeutic potential for human diseases. In addition, Q-tRNA is reported to promote Dnmt2-driven tRNAAsp cytosine-5 methylation at anticodon position 38 (m5C38) (Tuorto et al. 2018).

Cytosine-5 methylation

Cytosine-5 methylation (m5C) is a prominent modification in diverse RNA species, with important implications in cell physiology and metabolism (Chen et al. 2016a, b; Zhang et al. 2018; Huang et al. 2021). Currently, Nol1/Nop2/SUN domain methyltransferases (NSUN2, NSUN3, and NSUN4) and DNA methyltransferase 2 (Dnmt2) are the known m5C-tRNA modifiers, in higher eukaryotes, methylating specific tRNAs at positions 48, 49, 50, 72 and at anticodon-loop positions 34 and 38, affecting their folding, stability, and function (Motorin et al. 2010; Haag et al. 2015; Trixl and Lusser 2019). NSUN2 is the best-characterized tRNA methyltransferase, with up-regulated expression in different tumors, that methylates tRNAs at positions 34, 48, 49, and 50 (Blanco et al. 2014; Hussain et al. 2013). Loss of NSUN2 increases angiogenin-mediated biogenesis of 5'tRNA fragments and reduces translation rates, linking cellular stress to neurodevelopmental disorders (Blanco et al. 2014). NSUN3 is another reported m5C34 writer for human mt-tRNAMet and, importantly, this m5C34 written by NSUN3 can be further converted by the RNA dioxygenase ALKBH1 to form 5-formylcytidine (f5C34) which is required for efficient mitochondrial translation (Nakano et al. 2016; Kawarada et al. 2017). ALKHB1 also mediates the formation of 5-hydroxymethyl-2΄-O-methylcytidine (hm5Cm) and 5-formyl-2΄-O-methylcytidine (f5Cm) at anticodon iposition 34 of cytosol tRNALeu (Kawarada et al. 2017). DNMT2 is a bona fide tRNA methyltransferase that installs m5C at position 38 (m5C38) in tRNAAspGUC, tRNAGlyGCC and tRNAValAAC (Goll et al. 2006; Huang et al. 2021; Li et al. 2021), and the pre-existing inosine at position 34 (I34) deposited by the adenosine deaminase tRNA specific (ADAT)2/3 complex and the C32U33(G/I)34N35(C/U)36A37C38 motif in the anticodon loop are required by efficient Dnmt2-tRNA recognition (Huang et al. 2021). Dnmt2 deletion causes no gross phenotype in mice, but the combined loss of NSUN2 and DNMT2 impairs cellular differentiation and protein synthesis (Blanco et al. 2014; Metodiev et al. 2014). Importantly, Dnmt2 relocates into stress granules under stress conditions and its depletion is known to reduce tRNA stability, and thus promoting biogenesis of tRNA-derived fragments (Schaefer et al. 2009; Zhang et al. 2018).

DNMT2-driven m5C-tRNA modification is thought to protect tRNA from ribonuclease cleavage, which is contradicted by the finding that DNMT2 depletion impedes the biogenesis of 5’tRNA fragments in sperm from males on a high-fat diet (HFD), preventing the intergenerational metabolic disorder susceptibility (Zhang et al. 2018). A possible explanation for this discrepancy is that sperm contains a unique repertoire of small non-coding RNAs, including microRNAs (miRNAs), small interfering RNA (siRNAs), piwi-associating RNA (piRNAs), transfer tRNA-derived small RNAs (tsRNAs) and small nucleolar RNAs (snoRNAs) (Wu et al. 2022), which are vulnerable to environmental insults, such as unhealthy diet, creating heritable epigenetic memories (Wu et al. 2022). Thus, the increased 5’ tRNA fragments in sperm likely result from HFD exposure rather than Dnmt2 depletion. Dnmt2 is necessary for installation of m5C mark to these fragments, which benefits their stability and function in transmitting paternally acquired traits (Chen et al. 2016a, b).

Cytosine-3 methylation

Cytosine-3 methylation at anticodon position 32 (m3C32) in cytoplasmic tRNAsThr/Ser is conserved in eukaryotic species and, in mammals, m3C32 in tRNAArgCCU/UCU and mitochondrial (mt-)tRNAs are also identified (Huang et al. 2022; Kleiber et al. 2022). The installation of m3C32 is catalyzed by methyltransferase, Trm140/141 in Saccharomyces cerevisiae and METTL2/6 in mammals, and impairment in m3C32 has been implicated in tumor growth, pluripotency, and developmental anomalies (Ignatova et al. 2020; Lentini et al. 2020; Schöller et al. 2021; Mao et al. 2021). METTL2 methylates m3C32 in tRNAThrAGU, tRNAThrUGU, and tRNAArgCCU; while METTL6 is the tRNASer-specific m3C32 modifier (Ignatova et al. 2020). Deletion of METTL6 reduces m3C level by half in tRNASer isoacceptors and impairs ribosome occupancy and translation, which thereby compromises pluripotency of mouse embryonic stem cells and growth of hepatocellular carcinoma cells (Ignatova et al. 2020). In addition, METTL6 null mice display metabolic disorders and reduced energy turnover (Ignatova et al. 2020).

Recently, the methyltransferase METTL8, thought of as a mRNA modifier, is identified to be mitochondrial matrix-associated for installing m3C32 in mt-tRNAs, as m3C modification in mt-tRNAs, but not in cytoplasmic tRNAs, is diminished by METTL8 knockout (Kleiber et al. 2022). METTL8 has multiple isoforms due to alternative splicing and, thus, being targeted into distinct cellular compartments, with METTL8-Iso1 primarily enriches in mitochondria (Huang et al. 2022). Mammalian mitochondrial genome encodes 22 tRNAs for the decoding of mitochondrial building blocks and 18 types of chemical modifications in those tRNAs installed by tRNA-modifying enzymes have been identified (Suzuki et al. 2020; Schöller et al. 2021). METTL8-driven m3C32 modification, which facilitates the optimal translation of mt-tRNAThr/SerUCN-dependent codons, albeit is unnecessary for their aminoacylation, is promoted by specific anticodons (U34 and G35), other modifications at position 37 (t6A37 and (ms2)i6A37) and the mitochondrial seryl-tRNA synthetase SARS2 (Schöller et al. 2021; Huang et al. 2022; Kleiber et al. 2022). That high METTL8 expression and increased mt-tRNASerUCN m3C32 modification correlate with poor patient survival in pancreatic cancers is recently reported, suggesting an addiction of pancreas cancer to METTL8 (Schöller et al. 2021). Indeed, METTL8 knockout triggers mitoribosome stalling on mt-tRNASerUCN codons, leading to compromised mitochondrial function and reduced cell proliferation in pancreas carcinoma cell PANC-1, due to impaired translation of NADH dehydrogenase subunit (ND)1 and ND6 (Schöller et al. 2021).

N6-isopentenyladenosine and N6-methyl-threonylcarbamoyladenosine modifications

Interestingly, m3C32 methylation in Escherichia coli (E.coli) is shown to be regulated by other modifications at adjacent position 37, such as N6-isopentenyladenosine (i6A) and N6-methyl-threonylcarbamoyladenosine (m6t6A) (Zhou et al. 2015). i6A and m6t6A, the adenosine modified with other chemicals, are conserved tRNA modifications across species and are proposed to stabilize cognate codon-anticodon interactions (Boccaletto et al. 2018; Liaqat et al. 2020). i6A is shown to intervene epidermal growth factor receptor (EGFR) signaling activity through down-regulation of EGFR (Ciaglia et al. 2017). It has anti-proliferative and pro-apoptotic effects and triggers caspase-independent necroptosis in human glioblastoma cells (Navarra et al. 2020; Pagano et al. 2022), which suggests that targeting i6A could be a therapeutic strategy mitigating the malignancy of glioblastoma gultiforme, one of the most lethal brain cancers. A recent study reports that tRNA modifying enzymes, such as Trit1 and TrmO for anticodon modifications, and most tRNA modifications, such as i6A and m6t6A, are present in a sex-associated manner in mosquitoes, with more abundance in the females (Kelley et al. 2022). Mosquitoes are the most dangerous disease-carrying pests contributing to 17% of global infectious diseases causing millions of deaths each year (World Health Organization 2020). These findings suggest that targeting tRNA modification is a potential novel remediation strategy for mosquitoes control through intervening their growth and fecundity, as loss of t6A in fruit flies is shown to cause a phenotype of smaller larvae in them (Rojas-Benítez et al. 2017).

N1-methyladenosine modification

N1-methyladenosine (m1A), mono-methylation of adenosine moiety in N1 position, is a highly conserved modification known to target tRNAs that promotes their stability and proper folding. Loss of m1A modification on tRNALys induces the misfolding of tRNA, which thereby affects tRNALys function (Pan 2018). m1A in cytoplasmic tRNAs occurs at positions 9, 14, and 58, and m1A58-tRNA is ‘written’ by a methyltransferase complex composingof an RNA binding subunit TRMT6 and a catalytic TRMT61A and is ‘erased’ by the demethylase ALKBH1/3; while m1A in human mitochondrial tRNAs (mt-tRNAs) at positions 9 and 58 is deposited by TRMT10C and TRMT61B, respectively (Chujo and Suzuki 2012; Vilardo et al. 2012). Of note, ALKBH1 is shown to exhibit demethylation activity to erase m1A in mt-tRNAs (Kawarada et al. 2017). m1A-tRNA shows a higher preference for interacting with the elongation factor eEF1α to promote translation (Liu et al. 2016), and m1A58 in tRNA affects many aspects of cellular proliferation and metabolism. Recent evidence has linked the decreased expressions of TRMT61A and TRMT10C with hypo-m1A-methylation in 5xFAD mice, an Alzheimer's disease animal model. Deficiency in these m1A ‘writers’ significantly reduces the expression of mitochondrial tRNAs, including initiator tRNAMetCAT, and induces Alzheimer’s disease-related phenotype (Shafik et al. 2022), suggesting an involvement of m1A-mtRNAs in Alzheimer’s disease etiology.

TRMT6/TRMT61A-mediated tRNA methylation also implicates in tumourigenesis. HCC is characterized by high recurrence and heterogeneity, mainly due to the presence of hierarchically organized cancer stem cells (CSCs) (Meacham and Morrison 2013). In HCC patient tumor tissue and liver CSCs, remarkably increased m1A58 in tRNA is observed, resonating with the elevated expression in TRMT6 and TRMT61A, negatively correlating with patient survival. Deficiency in TRMT6/TRMT61A reduces m1A in a subset of tRNAs, leading to decreased expression of peroxisome proliferator-activated receptor δ (PPARδ) required for cholesterol synthesis, impairing liver CSC self-renewal and tumor growth due to inactivation of Hedgehog signaling (Wang et al. 2021a). As cholesterol metabolism is frequently dysregulated in malignancy (Nelson et al. 2013; Wang et al. 2018a, b), targeting it has been proposed as a therapeutic strategy for HCC (Jiang et al. 2019). Therefore, TRMT6/TRMT61A is also considered a promising therapeutic target for HCC.

The TψC arms and 3′ ends of certain cytoplasmic tRNAs, including tRNA3Lys, can be used as the primers for reverse transcription of retroviruses (Ruggero et al. 2014; Zhou et al. 2017; Fukuda et al. 2021). TRMT6-TRMT61A-driven tRNA3Lys m1A58 is shown to constitute as a stop site for reverse transcriptase, which thereby promotes the replication of HIV-1 and the production of HIV-1 proteins and virions (Fukuda et al. 2021). Interestingly, the Hoogsteen base-pair formed by m1A at position 58 and 5-methyluridine at position 54 (m5U54) can stabilize the tertiary structure of tRNA, TRMT6-driven m1A58 promotes m5U54 formation in tRNA3Lys, further supporting the existence of tRNA modification network (Zagryadskaya et al. 2003; Fukuda et al. 2021).

tRNA m1A58 specifically promotes the translation efficiency of cell-cycle regulators required for rapid proliferation. By facilitating the translation of Myc, a transcription factor that promotes cellular proliferation, TRMT61A-driven tRNA-m1A58 methylation constitutes a novel translational checkpoint for T cell activation (Liu et al. 2022). CD4+ T cells are critical for adaptive immune response in maintaining immune homeostasis and, upon antigen recognition, naive CD4+ T cells exit from quiescence state and undergo clonal expansion and differentiation into functional effector cells (Tan et al. 2017). TRMT61A and TRMT6 are up-regulated upon T cell activation, and TRMT61A deficiency reduces tRNA-m1A58 modification, resulting in disrupted CD4+ T cell proliferation and compromised immune function in the adoptive T cell transfer colitis model (Liu et al. 2022).

N7-methylguanosine modification

N7-methylguanosine (m7G) modification at position 46 in the tRNA variable loop is a conserved modification that promotes selective translation of transcripts enriched in m7G-tRNA-decoded codons (Orellana et al. 2021). In mammals, this modification is deposited by a complex of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (Wdr4). Increased expression of METTL1/Wdr4 in aggressive cancers is associated with cancer progression, poor prognosis, and chemoresistance (Lin et al. 2018; Chen et al. 2021, 2022; Dai et al. 2021; Orellana et al. 2021; Han et al. 2022; García-Vílchez et al. 2023a, b; Wang et al. 2023; Zhao et al. 2024). Targeting METTL1 may offer therapeutic potential for chemoresistant cancers. The gain-of-function of METTL1/WDR4 enhances a subset of tRNAs, including the isodecoder Arg-TCT-4–1, leading to malignant transformationthrough enhanced translation of cell-cycle progression mRNAs. Overexpression of m7G-tRNA Arg-TCT-4–1 can mimic the effects of METTL1/WDR4 overexpression (Orellana et al. 2021).

In the case of HCC, the fourth leading cause of cancer-related mortality (Villanueva 2019), reduction in METTL1/WDR4 activity attenuates the aggressive phenotype of HCC cells, presumably due to tRNA instability-induced defective translation of oncogenes (Huang et al. 2023). METTL1-driven tRNA m7G modification is shown to promote translation of genes involved in EGFR pathway and thereby confers HCC cells resistance to lenvatinib- a first-line chemotherapy drug for advanced HCC and vice verse (Huang et al. 2023). METTL1 and WDR4 are also significantly upregulated in intrahepatic cholangiocarcinoma (ICC), the second most common and devastating primary liver cancer, which is associated with poor patient survival (Dai et al. 2021). tRNA m7G modification in ICC ensures the expression of m7G-modified tRNAs, such as tRNALysCTT/TTT, and selectively drives the translation of oncogenic genes, including those involved in cell-cycle (CCNA2, CCND2, CDK6, and CDK8) and EGFR pathway (EGFR), contributing to ICC tumorigenesis and progression (Dai et al. 2021). More importantly, METTL1 has immunomodulatory property and emerges as an immunotherapeutic target of ICC which shows very low responsiveness to immune checkpoint therapy (Liu et al. 2023). METTL1 benefits the immunosuppressive tumour microenvironment of ICC through augmenting intratumoral accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in a chemokine-dependent mechanism. Co-blockade of METTL1 and the downstream chemokine pathway potentiates anti-PD-1 efficacy in ICC preclinical mouse models (Liu et al. 2023).

METTL1, located on chromosome 12q14.1, is frequently amplified in osteosarcoma, and METTL1/WDR4 in osteosarcoma promotes chemoresistance to doxorubicin and drives osteosarcoma progression, presumably by enhancing extracellular matrix remodeling (Wang et al. 2023). In nasopharyngeal carcinoma, the transcription factor Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT)-driven upregulation of METTL1/WDR4 promotes chemoresistance to cisplatin and docetaxel via Wnt/β-catenin signaling, favoring epithelial-mesenchymal transition (Chen et al. 2022). Highly expressed METTL1/WDR4 in esophageal squamous cell carcinoma (ESCC) is associated with poor patient survival. ESCC is one of the two main subtypes of esophageal cancer- a malignancy causing over 400,000 deaths worldwide annually (Bray et al. 2018). Knockout of METTL1/WDR4 decreases tRNA m7G modification in ESCC, which causes reduced translation of selective m7G-related codon enriched transcripts including the mechanistic target of rapamycin (mTOR), leading to hypoactivation of mTOR/Ulk1/autophagy, impeding ESCC tumorigenesis (Han et al. 2022). Resonated with the hyperactivation of mTOR in various types of cancers that promotes cancer progression (Hua et al. 2019), targeting METTL1 and mTOR/Ulk1/autophagy as a combination therapy therefore could be a promising strategy for ESCC treatment.

In lung cancer, the leading cause of cancer-related death, METTL1 is shown to promote cancer growth through increasing the expression of m7G-modified tRNAValAAC and tRNAProAGG and consequently leading to increased translation of a subset of oncogenic transcripts, such as cell-cycle regulator CCND3 (Ma et al. 2021).

5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification

The eukaryotic Elongator complex, beyond its roles in transcription elongation and protein acetylation, is shown to be involved in tRNA modifications (Miśkiewicz et al. 2011; Selvadurai et al. 2014; Gaik et al. 2023). ELP3 is the catalytic subunit of Elongator complex that functions as a tRNA U34-modifying enzyme catalyzing the formation of carboxymethyluridine at C5-position (cm5U) which is further converted to mcm5s2U to promote the decoding efficiency of specific codons (Selvadurai et al. 2014). The expression of ELP3 is decreased in the brain of Alzheimer's disease (AD) patients and amyloid mouse models and negatively correlates with amyloid plaque in AD, indicating that ELP3 down-regulation and tRNA hypomodification are cellular responses to amyloid pathology and that intervention of ELP3-driven tRNA modification may be a potential therapeutic avenue to restore neuronal function and proteostasis in AD (Pereira et al. 2024).

Loss of Elp3 impedes mcm5s2U modification of tRNA U34 in Aspergillus fumigatus which thereby compromises its metabolic homeostasis and virulence traits, the phenotypes of which can be rescued by overexpression of tRNAGlnUUG and tRNAGluUUC, two tRNAs with mcm5s2U modification (Zhang et al. 2022). Considering Aspergillus fumigatus is a human opportunistic fungal pathogen that causes diverse respiratory diseases, the importance of tRNA modification in shaping its virulence traits will provide insightful hints for the development of novel antifungal drugs.

RNA modification controls tsRNA biogenesis and activity

Production of functional tsRNAs from full-length tRNAs by stress-activated ribonucleases, including argonaute RISC catalytic component 2 (Ago2), Angiogenin (ANG), ELAC2, and RNase1, is a conserved cellular stress-rectifying mechanism to cope with environmental stress (Li et al. 2022). Distinct classes of tsRNAs across species have been identified and they are defined based on the cleavage site on mature and pre-tRNAs. Roughly they can be classified into two prominent types: 1) tRNA-derived stress-induced RNAs (tiRNAs, also known as 5′- and 3′ tRNA halves) that are 29–50 nucleotides in length cleaved in the anticodon loop, and 2) 5′- and 3′-tRFs that are 12–30 nucleotides in length derived from cleavage of mature or pre-tRNAs at various positions in D-loop and T-loop, respectively (Yu et al. 2020; Fu et al. 2023). tRFs can be further sorted into distal tRF (tRF-5: tRF-5a, tRF-5b, tRF-5c; tRF-3: tRF-3a, tRF-3b), internal tRF (i-tRF), pre-tRNA (tRF-1), and ‘other’ subtypes (Fig. 1) (Fu et al. 2023). Several databases are available for tsRNA exploration (Table 2). Table 2 Available tsRNA databases

Database	Characteristics	URL link	Reference	
tRFdb	A database for tsRNA	http://genome.bioch.virginia.edu/trfdb/	Kumar et al. 2015	
tDRmapper	A tool for naming, mapping, and quantifying tsRNA from human small RNA-seq datasets	https://github.com/sararselitsky/tDRmapper	Selitsky and Sethupathy 2015	
GtRNAdb 2.0	A source of tRNA identified in genomic context	http://gtrnadb.ucsc.edu/	Chan and Lowe 2016	
tRFBrowser	A database for exploring the chemical modifications in tsRNAs	http://rna.sysu.edu.cn/tRFfinder/	Zheng et al. 2016	
YM500v3 database	A database for integrated analysis of small RNAs in cancers	http://ngs.ym.edu.tw/ym500/	Chung et al. 2017	
MItochondrial and Nuclear TRF mapping (MINTmap)	A software package for identification of tsRNA from short RNA sequencing datasets	https://github.com/TJU-CMC-Org/MINTmap/)	Loher et al. 2017	
MINTbase v2.0	A database includes the mitochondrial and nuclear fragments from The Cancer Genome Atlas (TCGA) projects	http://cm.jefferson.edu/MINTbase/	Pliatsika et al. 2018	
SPORTS1.0	A tool for profiling and annotating ncRNAs optimized for tsRNA and rRNA	https://elkssl99cd2175108d157588c04758296d1cfclib.link.nbu.edu.cn:8443/junchaoshi/sports1.0	Shi et al. 2018	
tRFexplorer	A database for quirying tsRNA profile in TCGA samples	https://trfexplorer.cloud/	La Ferlita et al. 2019	
OncotRF	A database for exploration of cancer-associated tsRNAs	http://bioinformatics.zju.edu.cn/OncotRF	Yao et al. 2020	
BBcancer	A source of expression atlas for diverse RNA types, including tRFs	http://bbcancer.renlab.org/	Zuo et al. 2020	
tsRBase	A database for the function and expression of tsRNA across species	http://www.tsrbase.org/search.php	Zuo et al. 2021	

The regulatory mechanisms underlying tRNA fragmentation encompass the susceptibility of tRNAs to endonucleolytic cleavage, the determination of cleavage sites, and the selective retention of specific fragments following enzymatic nicking (Kuhle et al. 2023). Compelling evidence has demonstrated that tRNA modification is an important determinant for tRNA fragmentation (Fig. 3).Fig. 3 tRNA modification actively regulates tRNA fragmentation. Generally, posttranscriptional modifications on tRNAs render them resistant to endonucleolytic cleavage, protecting tRNAs from fragmentation (Tuorto et al. 2012; Guzzi et al. 2018; Cosentino et al. 2018; Zhang et al. 2018; Wang et al. 2018a, b; Chen et al. 2019; Vitali and Kiss 2019; Rashad et al. 2020; van Ingen et al. 2022; García-Vílchez et al. 2023a, b). In rare cases, for example, FTSJ1-mediated NmG34 is shown to promote tRNA gragmentation

Dnmt2/NSUN2-driven m5C modification in tRNAs also renders them the resistance to Angiogenin (ANG)-mediated endonucleolytic cleavage (Schaefer et al. 2009; Tuorto et al. 2012; Blanco et al. 2014; Zhang et al. 2018). NSUN2 deficiency increases apoptosis in neurons, presumably due to hypo-m5C48/49-methylation in tRNAs and increased biogenesis of ANG-mediated tRNA halves, as the oxidative stress-induced neurotoxicity in NSUN2-deficient mouse brain is subverted by ANG inhibition (Blanco et al. 2014). Q34, m3C and m1A modifications also have inhibitory effects on ANG-mediated tRNA cleavage (Chen et al. 2019; Rashad et al. 2020). TRMT10A-mediated tRNAGln m1G9 modification is reported to stabilize tRNAGln, as TRMT10A deficiency causes accumulation of 5′ tsRNAGln, leading to apoptosis in pancreatic β-islet cells (Cosentino et al. 2018). m7G modification is shown to protect tRNAs from endonucleolytic cleavage and thereby constitutes a pro-cell-survival mechanism (Dai et al. 2021; Orellana et al. 2021; Guzzi et al. 2022; García-Vílchez et al. 2023a, b). In acute myeloid leukemia (AML), one among the most lethal hematologic malignancies characterized by impaired differentiation commitment for myeloid lineages, METTL1 depletion destabilizes tRNAs and promotes biogenesis of tsRNAs, leading to impaired leukeamogenesis of AML cells (Orellana et al. 2021; Zhao et al. 2024), the phenotype of which can be reproduced by transfection of tRNAs retrieved from METTL1-depleted AML cells (Zhao et al. 2024).

Certain modifications have both inhibitory and stimulatory effects on tRNA cleavage. 2’-O-methylation can enhance the stability of tRNAs including tRNAMet, protecting them against site-specific cleavage, and inhibiting tsRNA biogenesis (Chan et al. 2009; Vitali and Kiss 2019; Angelova et al. 2020; van Ingen et al. 2022). 2’-O-methylation is reported to be dynamically regulated by stress conditions (Galvanin et al. 2020), further supporting the regulation of stress-responsive tsRNA biogenesis by 2’-O-methylation. 2’-O-methylation in tRNAPhe however is required for its SAMD9-mediated cleavage (Zhang et al. 2023b).

Functional diversity of tsRNAs in malignancies

tsRNAs are multifacted cellular signaling molecules. They halts global protein synthesis by dismantling the components of translation initiation complex from the 5' cap of mRNAs, allowing cells to survive under stressed conditions (Ivanov et al. 2011; Blanco et al. 2014). Induction of ribosome stalling and interaction with the aminoacyl-tRNA synthetase represent another mechanisms by which tsRNA inhibits global translation (Mleczko et al. 2018; Gonskikh et al. 2020). Moreover, the GG dinucleotide in 5′-tRFs and the G-quadruplex structure assembled by 5′-tiRNAs also can inhibit protein synthesis (Sobala and Hutvagner 2013 Ivanov et al. 2014). It is however shown that tsRNA can also enhance protein synthesis in vertebrates. For example, by selectively binding to the coding sequence and 3' UTR sequence of RPS28 and RPS15 mRNAs, tRNALeuCAG-derived 3'tsRNA promotes their translation and thereby maintaining ribosome biogenesis (Kim et al. 2017, 2019). The binding of 5′ tsRNAGln to multisynthetase complex (MSC) is reported to increase the translation of ribosomal proteins (Keam et al. 2017). In another study, the binding of 3′-tiRNAThr to ribosome and polymer is found to enhance mRNA loading into ribosome, thereby promote translation (Fricker et al. 2019). Importantly, having complementary sequences to mRNAs, tsRNAs, if not all, are appreciated as miRNA-like regulatory molecules that target genic mRNAs to regulate protein synthesis (Martinez et al. 2017). In these scenarios, the functional plasticity of tsRNAs is fulfilled by competing with other molecules for the binding of target proteins and/or mRNAs. In addition to translational regulation, tsRNAs exhibit many other striking regulatory activities, such as retrotransposon inactivation, gene silencing, and intergenerational inheritance (Martinez et al. 2017; Su et al. 2020). Thus, tsRNAs could be potential better-than-miRNA disease biomarkers as distinct signatures of extracellular tsRNAs are observed in plasma from patients on cardiopulmonary bypass (Li et al. 2022) (Table 3). Figure 4 depicts some representative activities of tsRNAs. Table 3 tsRNA in cancer progression and chemoresistance

Cancer	tsRNAs	Main findings	Reference	
Breast cancer	5'-SHOT-RNAs	Promotes cell proliferation	Honda et al. 2015	
tRF-0009

tRF-7336

	Promote doxorubicin chemoresistance probably through the activation of STAT3 signaling pathway	Wang et al. 2010

Cui et al. 2019

	
tRF-27-ZDXPHO53KSN

tRF-30-JZOYJE22RR33

	Being potential contributors to chemoresistance of to trastuzumab	Sun et al. 2018	
5'-tiRNAVal	Suppresses breast cancer malignancy through inactivation of FZD3/Wnt/β-catenin signaling pathway	Mo et al. 2019	
i-tRFs from tRNAGly/Asp/Tyr/Glu	i-tRFs can directly bind to YBX1, restraining YBX1’s accessibility to oncogenic transcripts, thereby suppressing the aggressiveness of breast cancer	Fujita et al. 2005

Goodarzi et al. 2015

	
tRF-46 tRF-47	Being potential contributors to the chemoresistanceto lapatinib	Tao et al. 2021	
ts-112	Inhibition of ts-112 reduces the aggressiveness of breast cancer cells	Balatti et al. 2017	
Lung cancer	tRF-46

tRF-47 tRF-101

	ts-46 is associated with hyper-activation of ILK, integrin and mTOR signaling pathways;

tRF-46 and tRF-101 are associated with inactivation of PTEN signaling; tRF-46/47 suppresses the growth and survival of lung cancer cells

	Balatti et al. 2017	
Colorectal cancer	tRF-3022b	tRF-3022b stabilizes LGALS1 to promote cell survival and, when delivered into macrophages, suppresses polarization of tumor-associated macrophages required for anti-tumor immunity through stabilizing MIF	Lu et al. 2022	
Colorectal cancer	5’tiRNAHisGTG	5’tiRNAHisGTG targets the 3’UTR of LATS2, inhibiting LATS2 expression, which impairs hippo signaling pathway and thereby initiates pro-proliferation and anti-apoptosis programs to promote CRC progression	Tao et al. 2021	
tRF-3001a	The tumor suppressor tRF-3001a interacts with the 3’ UTR of Jag2, inhibiting Jag2 expression, which inactivates Notch signaling to impair cancer stem cell function and CRC progression	Huang et al. 2017	
Chronic lymphocytic leukemia	ts-3676	ts-3676 associates with Ago and targets the 3’ UTR of TCL1 mRNA, leading to a down-regulation of TCL1, the overexpression of which can promote the aggressive phenotype of CLL	Balatti et al. 2015

Pekarsky et al. 2016

	
Epithelial ovarian cancer	3'U-tRFValCAC	Increases the aggressiveness of ovarian cancer cells	Panoutsopoulou et al. 2023	
Prostate cancer	5' tRFs	Promotes the translation of key regulators of tumor suppression and immune response that reshapes TME and sensitizes cancer cells to chemotherapy, enabling a better anti-tumor immunity	García-Vílchez et al. 2023a, b	
5'-SHOT-RNAs	Promotes cell proliferation	Honda et al. 2015	
Gastric cancer	tRF-Val	Mediates nuclear transportation of EEF1A1, promoting MDM2-mediated ubiquitylation of p53, which tags p53 for proteasomal degradation, thereby promoting cancer progression by impairing the downstream signaling pathway of p53	Cui et al. 2022	
Papillary thyroid cancer	tiRNA-Gly	tiRNA-Gly binds to RBM17 and stabilizes RBM17, which leads to RBM17-dependent exon 16 skipping of MAP4K4, promoting cancer progression via MAPK pathway	Han et al. 2021	
Acute leukemia	tRF-5 s	Promotes the differentiation of haematopoietic stem and progenitor cells through repressing the translation of transcripts with pyrimidine-enriched sequence	Guzzi et al. 2022	

Fig. 4 Representative functions of tsRNAs. tsRNAs can regulate gene expression at multiple layers. They can either sequester RNA-binding proteins to influence their activities on mRNA or promote ribosome occupancy at mRNA through enhancing the translation of ribosomal proteins. They also can function via the RNA interfering mechanism and more importantly, certain tsRNAs are implicated in intergenerational epigenetic inheritance of paternally acquired phenotypes

tsRNAs with pro-tumor activity

tsRNAs can function as pro-tumor factors that promote tumor growth and aggressiveness. While deregulation of tsRNAs is commonly associated with human cancers (Balatti et al. 2017; Zhang et al. 2019; Su et al. 2020; Fu and Xu 2022; Fu et al. 2023; Zhou et al. 2024), whether and how tsRNA influences carcinogenesis are yet poorly explored.

In gastric cancer (GC), an upregulation of tRF-Val, a type of 3′-tRF, is observed, which is associated with tumor growth and invasion (Cui et al. 2022). By directly binding to EEF1A1, a chaperone molecule, tRF-Val mediates its nuclear transportation. In the nucleus, EEF1A1 interacts with MDM2, enhancing the interaction between the E3 ubiquitin ligase MDM2 and the tumor suppressor p53. Consequently, MDM2-mediated ubiquitylation tags p53 for proteasomal degradation, leading to impairment in the downstream signaling pathway of p53, which promotes GC progression (Cui et al. 2022).

In sex hormone-dependent cancers, a repertoire of sex hormone-dependent tRNA-derived RNAs (SHOT-RNAs) shows specific accumulation in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer (Honda et al. 2015). Those tsRNAs derived from ANG-mediated anticodon cleavage of tRNAs and the resultant 5'-SHOT-RNAs, but not 3'-SHOT-RNAs, have pro-proliferative activity (Honda et a. 2015), suggesting 5'-SHOT-RNAs are promising biomarkers of sex hormone-dependent cancers and importantly, they could be therapeutic targets in those patients with resistance to endocrine therapy.

Colorectal cancer (CRC) is the second and third most prevalent cancer in women and men, respectively, and is the second leading cause of cancer-related death globally (Dekker et al. 2019; Siegel et al. 2020). tRF-3022b is a pro-tumoral factor in CRC. tRF-3022b in CRC cells stabilizes Galectin 1 (LGALS1) to promote cell survival and, when delivered into macrophages, it suppresses polarization of tumor-associated macrophages required for anti-tumor immunity through stabilizing macrophage migration inhibitory factor (MIF) (Lu et al. 2022). Suppression of tRF-3022b induces macrophage polarization and attenuates tumor growth (Lu et al. 2022). In another study, the oncogenic activity of 5’tiRNAHisGTG, a tRNAHis-derived 5’tRNA half, in CRC is reported. 5’tiRNAHisGTG in CRC is up-regulated by the hypoxia/HIF1α/angiogenin (ANG) signaling axis (Tao et al. 2021). By targeting the 3’UTR of large tumor suppressor kinase 2 (LATS2), 5’tiRNAHisGTG inhibits LATS2 expression that shuts off the hippo signaling pathway, which thereby initiates pro-proliferation and anti-apoptosis programs to promote CRC progression (Tao et al. 2021).

In papillary thyroid cancer, a 33 nt tiRNA-Gly shows the highest up-regulation, which is positively associated with an advanced pathologic grade and lymph node metastasis (Han et al. 2021). A direct binding of tiRNA-Gly to the splicing-related RNA-binding protein RBM17 not only increases RBM17 abundance through inhibition of ubiquitin/proteasome-dependent degradation but also promotes its translocation from the cytoplasm into the nucleus. This leads to RBM17-dependent exon 16 skipping of the oncogene MAP4K4, promoting the malignant progression of cancers via MAPK pathway, the phenotypes can be reversed by loss of tiRNA-Gly (Gao et al. 2017; Han et al. 2021).

In chronic lymphocytic leukemia (CLL), the most common type of human leukemia, and lung cancer, their is an observed down-regulation of tRNASer-derived ts-4521 and tRNAThr-derived ts-3676. In addition, several site mutations in ts-4521 and ts-3676 in lung cancer are identified (Pekarsky et al. 2016). ts-3676 associate with Ago and targets the 3’ UTR of TCL1 mRNA, leading to a down-regulation of TCL1, the overexpression of which promote the aggressive phenotype of CLL (Balatti et al. 2015). In another study, pre-tRNAHis-derived ts-43 and ts-44 are shown to be down-regulated in CLL. Additionally, 964 mature tRFs are up-regulated, while 701 are down-regulated, suggesting tha tRFs may have oncogenic and/or anti-tumor activities in CLL (Veneziano et al. 2019). Cardiovascular dysfunction is a common comorbidity in patients with lung cancer. In a mouse model of lung cancer, 38 differentially expressed tRNA-derived small RNAs (tsRNAs, 22 up-regulated and 16 down-regulated) are identified in cardiac tissue and some tsRNAs show exclusive expression in there (Wu et al. 2023), suggesting that tsRNA could be potential biomarkers and novel targets for disease therapeutics (Fu et al. 2023). However, whether these reprogrammed tsRNAs are bona fide contributors to the disease pathogenesis and, if so, what the molecular mechanisms may be involved warrant further investigations.

The involvement of tsRNAs in RNA interference, through in association with Ago, is supported by recent studies reporting that Dicer-dependent tsRNAs guide the intronic targeting of Ago2 to target transcripts, repressing their expression via nuclear nascent RNA silencing (Green et al. 2020; Di Fazio et al. 2022). Transfection of synthetic single-stranded tsRNAs that target the proto-oncogenic factors, EGFR, B-cell lymphoma-2 (Bcl2), and lncRNA INC00665, efficiently decreases their expressions and induces anti-proliferative signals in cancer cells (Di Fazio et al. 2022).

In epithelial ovarian cancer (EOC), elevated intratumoral 3'U-tRFValCAC level is associated with a higher risk of cancer progression and worse outcomes following platinum-based chemotherapy (Panoutsopoulou et al. 2023). 3' U-tRFValCAC is derived from pre-tRFValCAC and its overexpression significantly increases the aggressiveness of ovarian cancer cells (Panoutsopoulou et al. 2023).

tsRNAs with anti-tumor activity

The anti-tumor activity of tsRNAs has also been documented. In CRC patients, tsRNAs such as tRF-3001a (miR-1280, derived from tRNALeu and pre-miRNA) and tRF-3022b exhibit increased abundance (Huang et al. 2017; Lu et al. 2022). By interacting with the 3’ UTR of Jag2, the tumor suppressor tRF-3001a inhibits Jag2 expression and thus, inactivating Notch signaling to compromise cancer stem cell function and CRC progression (Huang et al. 2017). The anti-tumor activity of tRF-3001a is supported by the case of tRF-3027b (also known as miRNA-CU1276) in B-cell lymphoma. tRF-3001a, a Dicer-dependent tRF-3 from tRNAGlyGCC, is abundant in normal germinal center B cells but with decreased expression during malignant transformation of B cells and, when overexpressed, it suppresses the proliferation of lymphoma cells by down-regulating RPA1 via a miRNA-like mechanism (Maute et al. 2013).

Another example is the tRNAVal-derived 5’ tRNA half (5'-tiRNAVal) in breast cancer. 5'-tiRNAVal shows significant down-regulation in breast cancer, which is associated with lymphatic metastasis in breast cancer, and its overexpression suppresses breast cancer malignancy through inactivation of FZD3/Wnt/β-catenin signaling pathway (Mo et al. 2019). The internal tRFs (i-tRFs) derived from the anticodon loop of tRNAGly/Asp/Tyr/Glu also have tumor-suppressive activity in breast cancer cells. These tumor-suppressive i-tRFs can compete with various oncogenic transcripts for YBX1 binding. YBX1 is up-regulated in various cancers, including breast cancer (Fujita et al. 2005). That said, upon induction, they restrain the accessibility of YBX1 to those transcripts that cause their destabilization, which suppresses the aggressive behavior of breast cancer (Goodarzi et al. 2015).

METTL1 deficiency-driven biogenesis of 5' tRFs shifts the translation program to favor the expression of key regulators of tumor suppression and immune response, reshaping the tumor microenvironment and enhancing chemotherapy sensitivity, which leads to a better anti-tumor immunity in prostate cancer (García-Vílchez et al. 2023a, b). This finding is reminiscent of the report that increased biogenesis of stress-induced tsRNAs, due to loss of NSUN2-mediated m5C modification in tRNAs, renders cells hypersensitive to cytotoxic stress and blocks tumor regeneration after the chemotherapy with 5-fluorouracil (Blanco et al. 2016).

A recent study indicates that pseudouridylation of tRNAAla/Cys/Val-derived mini 5′ terminal oligoguanine-containing tRFs (mTOG or tRF-5 s) promotes the differentiation of haematopoietic stem and progenitor cells in patients with myelodysplastic syndrome, who are at high risk for acute leukemia (AML), by selectively repressing the translation of transcripts with pyrimidine-enriched sequence (PES) (Guzzi et al. 2022). PUS7-driven Ψ of tRFs constitutes a translation control mechanism for hematopoietic stem cell fate commitment (Guzzi et al. 2018). Notably, myelodysplastic syndrome is featured by a loss of PUS7. Ψ-driven direct binding of mTOG and polyadenylate-binding protein cytoplasmic 1 (PABPC1) hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1). This dysregulation increases the translation of PES-containing transcripts, linked to leukaemogenesis and poor patient survival (Guzzi et al. 2022).

tsRNAs in cancer chemoresistance

Recent evidence has documented the roles of tsRNAs in cancer chemoresistance. With significant up-regulation, tRNAGlyGCC-derived tRF-0009 and tRF-7336 are shown to promote doxorubicin chemoresistance in triple-negative breast cancer (TNBC) probably through activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway (Wang et al. 2010; Cui et al. 2019). Interestingly, inhibition of STAT3 mainly restores chemosensitivity to doxorubicin, but not cisplatin, of Adenomatous Polyposis Coli (Apc)Min/+ breast cancer cells featuring STAT3 hyperactivation (VanKlompenberg et al. 2017). In human epidermal growth factor receptor-2 (HER2)-positive breast cancer, trastuzumab-based chemotherapy achieves poorer outcomes in those patients with higher expression of tRF-27-ZDXPHO53KSN and tRF-30-JZOYJE22RR33, suggesting these tsRNAs are potential contributors to trastuzumab resistance (Sun et al. 2018).

In CLL and lung cancer, certain tsRNAs such as tRF-46, tRF-47, and tRF-101 are down-regulated (Balatti et al. 2017). tRF-46 is associated with hyper-activation of integrin-linked kinase (ILK), integrin, and mTOR signaling pathways, while tRF-46 and tRF-101 are associated with phosphatase and tensin homolog (PTEN) signaling inactivation (Balatti et al. 2017). Overexpression of tRF-46 and tRF-47 inhibits lung cancer cell growth and survival (Balatti et al. 2017). ILK is a serine/threonine protein phosphatase that promotes resistance to cisplatin and gemcitabine in lung adenocarcinoma (Zhao et al. 2015; Zhang et al. 2020b). Integrin is a transmembrane protein that serves as a marker of lung, breast, and pancreatic carcinomas (Seguin et al. 2014). Integrin is an activator of ILK that promotes cisplatin resistance (Zhao et al. 2015). It also promotes CSC self-renewal and resistance to EGFR receptor tyrosine kinase inhibitors (EGFR-TKIs) like erlotinib via the KRAS-RalB-NF-κB signaling (Seguin et al. 2014). Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling is known to promote chemoresistance in diverse human cancers (Wu et al. 2019). PTEN, a potent tumor suppressor, negatively regulates mTOR activity, and its deficiency leads to resistance to EGFR-TKIs in lung adenocarcinoma and resistance to paclitaxel in non-small cell lung cancer (Balatti et al. 2017; Zhong et al. 2017; Sun et al. 2019). All this evidence suggests that the down-regulation of these tsRNAs is a potential underlying mechanism of chemoresistance in CLL and lung cancers (Fig. 5).Fig. 5 Schematic illustration of the activities of tsRNAs in cancer biology. tsRNAs have pleiotropic biological effets, modulating both tumor development and chemotherapy efficacy. Of note, i-tRFs can directly bind to YBX1, restraining YBX1’s accessibility to oncogenic transcripts, thereby suppressing the aggressiveness of breast cancer

Therapeutic potential of tRNA and tsRNA

Dysregulation of tRNAs and tsRNAs significantly contributes to disease pathogenesis, but tRNA/tsRNA-based therapies for in vivo treatment are still in early development. Translating research findings from mice to humans for clinical use remains a long process.

Pioneering studies have demonstrated that, by a fine-tuning alternation in tRNA sequence that modulates its physicochemical property, native tRNAs can be modified into suppressor tRNAs that efficiently recode nonsense mutation-caused premature termination codon (PTC) with correct or near-cognate amino acid (Buvoli et al. 2000; Lueck et al. 2019; Wangen and Green 2020; Albers et al. 2023). Decoding of PTC leads to premature protein truncation, which is an underlying mechanism for many genetic diseases. Nonsense mutation in CDH1/E-cadherin is observed in 21.3% of individuals with hereditary diffuse gastric cancer, and synthetic suppressor-tRNA is shown to rescue the expression of full-length CDH1/E-cadherin being properly assembled into adhesion complex in the cells carrying PTC in CDH1/E-cadherin (Bordeira-Carriço et al. 2014). Intravenous or intratracheal administration of lipid nanoparticle (LNP)-encapsulated suppressor tRNAs in mice restores read-through of disease-causing PTCs, inducing functional recovery of those PTC-containing genes through cognate amino acid replacement, without causing discernible read-through at endogenous native stop codons (Albers et al. 2023). Lueck et al. reveal that the anticodon-engineered transfer RNAs (ACE-tRNAs) display high potency in targeted PTC suppression in mice that rescues the faithful decoding of various PTC‐containing genes with limited interaction with native translation termination codons (Lueck et al. 2019).

As to the in vivo therapeutic potential of tsRNAs, HC83 a tRNAGlnUUG-derived 3′-tRF from ginseng is reported to promote cardiomyocyte survival in vitro after hypoxia/reoxygenation, a model of human ischemic heart disease (IHD), and ameliorate ischemic/reperfusion-induced myocardial infarction in vivo (Hu et al. 2022). Mechanistically, HC83 maintains cytoskeleton integrity and mitochondrial function and, by binding to and repressing myocardial infarction-associated transcript (MIAT) a lncRNA that targets vascular endothelial growth factor A (VEGFA), it up-regulates VEGFA to promote cardioprotective angiogenesis in IHD (Yan et al. 2015; Hu et al. 2022). Importantly, HC83 exhibits > 500-fold more cardioprotective effects than metoprolol against ischemia/reperfusion injury (Hu et al. 2022). These studies suggest that tRNA-based PTC therapeutic is a promising strategy, with high safety and efficacy, for the treatment of human disease.

Short tandem target mimic (STTM), which consists of two short sequences that mimick the small RNA target elements separated by a link of optimized size (48–88 nucleotides in length), emerges as a powerful tool for inducing degradation of target small RNAs, primarily miRNA in plants, by RNA-degrading nucleases (Yan et al. 2012). STTM has been shown to efficiently block the function of 19 nt tRF-5 s in Arabidopsis thaliana. tRF-5 s constitute miRNA-like regulatory small RNAs in targeting the transcripts of transposable elements (TEs) which is deleterious to genome stability (Martinez 2018). tRF-5 s form a complex with AGO1, which specifically cleaves endogenous TE transcripts, maintaining TEs at a slienced state (Martinez et al. 2017). Sequestering MetCAT 19 nt tRF-5 s using MetCAT-STTM strategy leads to a less cleavage of Athila6A mRNA, a TE transcript that is predicted to be targeted by MetCAT-derived 19 nt tRF-5 s (Martinez et al. 2017). It is thus expected that STTM will be an important technology for exploring tsRNA function and for therapeutic applications in humans.

Conclusions and outlooks

While with great clinical significance, our knowledge of tRNA modifications however is still limited due to, in part, their dynamicity in response to different stimuli and the complexity of tRNA biology highlighted by the enigmatic world of tsRNAs which have copious extra-translational functions. In addition, despite the deregulation in tRNA modification and tsRNA biogenesis being linked to human diseases and resistance to cancer treatment, their biological functions are poorly understood. This review explores recent evidence that addresses the molecular mechanisms of clinically relevant tRNA modifications and tsRNAs, emphasizing their potential as biomarkers and therapeutic targets for human diseases.

Our current evidence has appreciated the promising therapeutic potency of tRNA/tsRNA-based therapy, this strategy however has not reached the translational stage, largely because of its known and/or possible unwanted side effects (Kiselev et al. 2002; Porter et al. 2021). Any therapy aiming at induction of the de novo expression of deregulated gene may cause uncontrolled gene overexpression or immune response, and this toxicity effect is indeed observed in tRNA-based therapy (Limberis et al. 2007; Mendell et al. 2010; Bönnemann et al. 2023; Lek et al. 2023). The development of more animal models that mimic a given human disease will provide valuable tools for evaluation of the therapeutic regime and impact of tRNA/tsRNA-based therapy on physiology. Another hindrance to tRNA/tsRNA-based therapy is our incomplete knowledge of posttranscriptional modifications on the biological activities of tRNA and tsRNA. The synthesized tRNA/tsRNA, if without certain modification(s), may pose totally different spatial structure and varied activities. That said, the synthesized molecule may not exactly mimic the activities of its endogenous counterpart, which should be aware of in future investigations.

Evidence suggests that ancestral environmental exposures and life experiences may create heritable epigenetic memories, leading to intergenerational effects via germline transmission involving tRNA modifications and tsRNAs (Chen et al. 2016a, b; Sharma et al. 2016; Zhang et al. 2018; Zhang et al. 2019; Galan et al. 2020). Injecting purified or synthetic tsRNAs reprogrammed by paternal exposures into naive zygotes can recapitulate the pathologies seen in offspring of exposed fathers (Chen et al. 2016a, b; Sarker et al. 2019; Zhang et al. 2021). As tRNA modifications and tsRNA biogenesis are sensitive to environmental stress and cellular metabolic status, understanding tRNA and tsRNA expression and modifications, as well as their roles in inheriting ancestrally acquired traits, will be a significant focus in the field of reproductive biology.

Technical challenges complicate the identification of tsRNAs through expensive sequencing methods, as pretreatment processes that remove modifications can affect their stability and lead to unreliable data. Notably, 5’ and 3’ tRNA halves mainly exist as stable nicked tRNA complexes in biofluids, including serum plasma, raising the question about whether tsRNAs function independently or as nicked tRNAs with possible hidden roles (Costa et al. 2023). It is likely that rebinding to their partners after separation constitutes a self-regulatory mechanism that restricts their activities on other effector molecules (Costa et al. 2023). In addition, Some longer tsRNAs function in an aptamer-like manner, differing from the linear-targeting model as of siRNA/miRNA (Kuhle et al. 2023). Emerging sequencing methods, such as PANDORA-seq, CPA-seq, and cP-RNA-seq, have led to the discovery of previously identified tsRNAs due to their modifications (Table 4). While the field of tsRNA has been recently growing, in some cases detected tRNA-derived fragments might only appear as degradation products or sequencing artifacts rather than having a real physiological role. Developing more advanced and cost-friendly technologies to decipher tsRNA sequences and modifications with naive molecular nature, along with artificial intelligence (AI)-powered prediction, will enhance our understanding of tRNA functionality and advance pharmaceutical engineering. A standardized nomenclature for tsRNAs is also essential, as certain tsRNAs can derive from different tRNAs, and their naming conventions may confuse readers. Table 4 Some high-throughput methods for tRNAome study

Method	Key features	Reference	
mim-tRNAseq	1. A modification-induced misincorporation tRNA sequencing workflow that enables preparation of full-length cDNA library from endogenously modified tRNA, accurately quantifying tRNA abundance, modification, and aminoacylation in any organism with a defined genome

2. Provides a comprehensive methodology for analysis of interdependence between modifications within a same tRNA transcript

	Behrens et al. 2021	
CPA-seq	1. A Cap-Clip acid pyrophosphatase, T4 polynucleotide kinase, and AlkB/AlkB-facilitated small ncRNA sequencing for profiling of small ncRNAs with nucleoside methylation and terminus multiplicity

2. Full-length tRNA degradation of caused by AlkB treatment during library preparation may contaminate CPA-seq reads

Unable to capture a full spectrum of RNA molecules (e.g. NAD-capped RNA)

	Wang et al. 2021b	
PANDORA-seq	1. Combinational T4PNK and AlkB treatment enables the identification of modified sncRNAs

2. Pre-size selection corrects false-positive count of sncRNAs induced by AlkB treatment

3. Updated analysis pipeline provides direct mapping of tsRNAs and rsRNAs in relation to their sequence origin

4. Improvement is needed to avoid the repeated RNA extraction post enzymatic treatment

	Shi et al. 2021	
tRNA structure-seq	1. A workflow that integrates dimethyl sulfate probing, ultra-processive verse transcription, and mutational profiling, enabling determination of tRNA structure, abundance, and modification at single-nucleotide resolution

2. Provides useful information for analysis of structural heterogeneity among similar tsRNAs with varying terminal lengths

	Yamagami et al. 2022	
SLAC	1. SingLe-read Analysis of Crosstalks (SLAC) is a single-read tRNA analysis pipeline that simultaneously assesses tRNAome-wide networks of abundance, modifications, aminoacylation, and fragmentation using the same tRNA-sequencing data

2. SLAC leverages the richness of the tRNA-seq data and provides new insights on the coordination of tRNA properties

	Hernandez-Alias et al. 2023	
LIDAR	1. Ligation-independent detection of all types of RNA (LIDAR) constructs sequencing library from RNAs of any length and with any type of 3’ terminal modification, simultaneously quantifying non-coding and coding transcriptome

2. LIDAR captures RNAs from limiting amount of material with commercially available reagents for Smart-seq, without the need for removal of 3’ terminal modification

3. LIDAR is not applicable to single cell analysis due to the contamination of adapter dimers when RNA amount is less than 10 ng

4. 5’-tDRs-like reads generated by internal priming events on full-length tRNAs cannot be formally excluded

	Scacchetti et al. 2023	
Nano-tRNAseq	1. A nanopore-based technology for profilling of native RNA molecules without reverse transcription, enabling accurately quantification of tRNA abundance and modification in a single experiment

2. Reveals the crosstalk and inter-dependency between tRNA modifications in the same molecule

3. A double ligation of adapters at both 5′ and 3′ ends leads to an improved mapping of tRNAs at a single-molecule resolution

4. The reference FASTA set used in mapping step may cause bias in estimation of tRNA abundance

	Lucas et al. 2024	

In summary, emerging evidence shows that tRNA modifications and tsRNAs significantly affect human health and disease, but their regulatory mechanisms are largely unexplored. Future research will deepen our understanding of tRNA's role in disease and guide the development of tRNA/tsRNA-based therapies to enhance the quality of life for those affected by tRNA modopathy.

Acknowledgements

We thank all the scientists in the field of tRNA biology for their dedicated studies leading to insightful discoveries.

Author contributions

Di Wu: Conceptualization, Data curation, Writing- original draft. Xiuling Li: Writing-review & editing. Faheem Ahmed Khan: Writing- original draft. Chenyang Yuan: Writing-review & editing. Nuruliarizki Shinta Pandupuspitasari: Writing-review & editing. Chunjie Huang: Conceptualization, Writing- original draft, Writing- review & editing. Fei Sun: Funding acquisition, Writing-review & editing. Kaifeng Guan: Writing-review & editing.

Funding

This work was supported by the Joint Research on Improved Agricultural Breeds from Henan Province (No. 2022020101), the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 22KJB180006), the National Natural Science Foundation of China (No. 82371613), the National Key Research and Development Program of China (No. 2021YFC2700200), and the National Natural Science Foundation of China (32302844).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Highlights

1. tRNAs are heavily decorated with chemical modifications required for their folding, stability and functions.

2. tRNA-derived fragments have many other extra-translational activities.

3. Dysregulation in tRNA modification and tsRNA biogenesis are associated with various human diseases.

4. tRNA-modifying enzymes and tsRNAs are promising diagnostic biomarkers and therapeutic targets.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Di Wu, Xiuling Li and Faheem Ahmed Khan contributed equally.
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