The purified Rad17 and Rad9-Hus1-Rad1 (9-1-1) complexes can form a stable co-complex in the presence of ATP, using Rad17-Rad9 interactions. From computer modeling studies, the Rad17 subunit of the complex is also proposed to interact with the C-terminus of Rad1, p36 with the C-terminus of Hus1, and p38 with the C-terminus of Rad9. A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phosphorylated, perhaps suggesting that 9-1-1 may regulate the recruiment of additional ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair.", "cellular_location": "nucleoplasm", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O60671-1", "Q99638-1" ], "evidence": [ { "id": "R-HSA-176264", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-176264" } ] }, { "id": "R-HSA-5684882", "name": "CHEK1 is recruited to resected DNA DSBs", "equation": "", "summary": "The recruitment of CHEK1 (CHK1) to resected DNA double-strand breaks (DSBs) and activation by ATR-mediated phosphorylation requires the presence of CLSPN (claspin) and TIMELESS:TIPIN protein complex. TIPIN simultaneously interacts with the RPA2 subunit of the RPA complex and CLSPN, allowing CLSPN to stably associate with resected DNA DSBs (Kemp et al. 2010). Phosphorylation of CLSPN at threonine T916 and serine S945 is needed for CHEK1 binding (Kumagai et al. 2003, Clarke and Clarke 2005). CLSPN phosphorylation at these sites is independent of CHEK1 (Bennett et al. 2008). Casein kinase 1 (CK1) was proposed as a kinase responsible for CLSPN phosphorylation (Meng et al. 2011) but the exact mechanism of this modification has not been established.
ATR-mediated phosphorylation of RAD17 on serine residues S635 and S645 is implicated in CLSPN recruitment to resected DNA DSBs and CLSPN phosphorylation (Wang et al. 2006). Also, phosphorylation of the RPA2 subunit of the RPA complex positively contributes to CHEK1 activation (Liu et al. 2012).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"O14757-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5684882",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5684882"
}
]
},
{
"id": "R-HSA-5684887",
"name": "Activation of CHEK1 at resected DNA DSBs",
"equation": "",
"summary": "CHEK1 (Chk1) is a checkpoint kinase activated during genotoxic stress. CHEK1 activation at resected DNA double-strand breaks (DSBs) involves ATR-mediated phosphorylation of CHEK1 serine residues S317 and S345 in the presence of claspin (CLSPN), TOPBP1, RAD17:RFC complex, RAD9:HUS1:RAD1 complex, TIMELESS:TIPIN complex, RPA complex and RHNO1 (Liu et al. 2000, Zhao and Piwnica-Worms 2001, Kumagai and Dunphy 2003, Sorensen et al. 2004, Wang et al. 2006, Kemp et al. 2010, Cotta-Ramusino et al. 2011, Liu et al. 2012). Following phosphorylation, CHEK1 dissociates from chromatin and phosphorylates target proteins involved in S/G2 checkpoint activation and/or homologous recombination repair (Smits et al. 2006). CLSPN needs to interact with chromatin only transiently in order to facilitate CHEK1 activation (Lee et al. 2005).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-176296",
"R-HSA-5684985"
],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"O14757-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5684887",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5684887"
}
]
},
{
"id": "R-HSA-5685011",
"name": "ATR activation at DNA DSBs",
"equation": "",
"summary": "ATR:ATRIP complex is recruited to resected DNA double-strand breaks (DSBs) via interaction with the RPA complex that coats single strand DNA (ssDNA) 3'-overhangs, but this is not sufficient for ATR to become catalytically active. ATR kinase activity requires the presence of the RAD17:RFC complex, RAD9:HUS1:RAD1 (9-1-1) complex and TOPBP1. RAD17:RFC loads RAD9:HUS1:RAD1 onto junctions of single strand and double-strand DNA (ssDNA-dsDNA junctions), present at resected DNA DSBs (Bermudez et al. 2003, reviewed by Sancar et al. 2004). TOPBP1 binds the C-terminal tail of RAD9, and is thus brought in the proximity of ATR, where it can activate it (Kumagai et al. 2006, Delacroix et al. 2007). The interaction of TOPBP1 and RBBP8 (CtIP) also contributes to TOPBP1 loading (Ramirez-Lugo et al. 2011). Phosphorylation of ATR at threonine residue T1989 may create a binding site for the BRCT domains of TOPBP1 (Liu et al. 2011). It is not clear whether T1989 of ATR is phosphorylated through autophosphorylation (Liu et al. 2011), as it does not conform to the SQ/TQ consensus, or by another kinase (Liu et al. 2013). RHNO1 (RHINO) protein simultaneously binds RAD9:HUS1:RAD1 complex and TOPBP1 and is required for the full catalytic activation of ATR (Cotta-Ramusino et al. 2011).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5685011",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5685011"
}
]
},
{
"id": "R-HSA-5685156",
"name": "ATR phosphorylates RPA2",
"equation": "",
"summary": "Activated ATR phosphorylates the RPA2 subunit of the RPA complex on serine residue S33. Phosphorylation of RPA2 at S33 likely stimulates additional RPA2 phosphorylation on CDK sites (S23 and S29) and DNA-PKcs (PRKDC) sites (S4, S8 and S21). DNA damage-regulated phosphorylation of RPA2 plays an important role in the progression of homologous recombination-directed repair of DNA double-strand breaks (DSBs) (Anantha et al. 2007, Liu et al. 2012, Murphy et al. 2014)",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5685156",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5685156"
}
]
},
{
"id": "R-HSA-5686642",
"name": "RAD52 promotes single strand annealing at resected DNA DSBs",
"equation": "",
"summary": "RAD52 promotes annealing of 3' ssDNA overhangs at resected DNA double-strand breaks (DSBs) through complementary regions. The complementarity between the two 3' ssDNA overhangs at resected DNA DSBs exists if 3' ssDNA overhangs contain direct repeats. While single strand annealing (SSA) requires significant homology between the annealed sequences it is nonetheless mutagenic. The parts of two 3' overhanging DNA single strands at resected DSBs that lie 3' to the annealed regions become displaced as flaps and subsequently excised. This results in the deletion (loss) of the DNA sequence lying between the two regions of homology used for SSA, as well as the deletion of one of the repeats used for annealing (Parsons et al. 2000, Van Dyck et al. 2001, Singleton et al. 2002, Stark et al. 2004, Mansour et al. 2008).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5686642",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5686642"
}
]
},
{
"id": "R-HSA-5686657",
"name": "ERCC1:XPF cleaves flaps generated by SSA",
"equation": "",
"summary": "The endonuclease complex ERCC1:XPF (ERCC1:ERCC4) is recruited to single strand annealing (SSA) sites of DNA double-strand break (DSB) repair through direct interaction between XPF (ERCC4) and RAD52 (Motycka et al. 2004). ERCC1:XPF cleaves the ssDNA flaps generated by displacement of non-complementary 3' parts of 3' ssDNA overhangs during RAD52-mediated annealing. The enzymatic activity of ERCC1:XPF is necessary for the completion of SSA (Motycka et al. 2004, Al-Minawi et al. 2008, Ahmad et al. 2008).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q92889-1",
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5686657",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5686657"
}
]
},
{
"id": "R-HSA-5693561",
"name": "RAD51 binds BRCA2 at resected DNA DSBs",
"equation": "",
"summary": "BRCA2 and RAD51 interact directly through the highly conserved BRC repeats in BRCA2 (Venkitaraman 2002). CHEK1-mediated phosphorylation of BRCA2 (at threonine residue T3387) and RAD51 (at threonine residue T309) modulates their binding (Sorensen et al. 2005, Bahassi et al. 2008). One BRCA2 can bind up to six RAD51 molecules, thus playing an important role in RAD51 nucleation at the dsDNA-ssDNA junction created by resection of DNA double-strand breaks (DSBs) (Liu et al. 2010, Thorslund et al. 2010, Jensen et al. 2010). After the nucleation step, additional RAD51 molecules bind the ssDNA and multimerize, forming RAD51 nucleoprotein filaments (Yang et al. 2005). BRCA2-mediated RAD51 loading displaces the RPA complex from 3' overhanging ssDNA at DSBs (Liu et al. 2010, Jensen et al. 2010), possibly with other RPA-bound proteins, such as ATR:ATRIP and complexes involved in ATR catalytic activation.
BRCA2-binding partner SEM1 (DSS1) directly facilitates RPA release from ssDNA and its replacement with RAD51 (Zhao et al. 2015).
The interaction with DNA is critical for BRCA2 function, and the protein contains two different DNA binding regions. The amino-terminal DNA-binding domain (NTD) (residue 267-350) consists of a zinc finger-poly(adenosine diphosphate-ribose) polymerase (PARP)-like domain and binds to different DNA structures (ssDNA, dsDNA, tailed DNA, and gapped DNA) with similar affinity (von Nicolai et al. 2016). The carboxy-terminal DNA-binding domain CTD (residue 2,474-3,190) is significantly more complex with three OB-folds and an apical 3 bundle helix on top of a tower domain preceded by a helical domain (Yang et al. 2002). The proposed breast and ovarian cancer cluster regions (BCCR and OCCR) overlap with the CTD (Rebbeck et al. 2015, Gayther et al. 1997). Several common pathogenic mutations (ClinVar database) and loss-of-function mutations are found in this region including K2630A, K2630D, D2723H.",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-5684878",
"R-HSA-5684880"
],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5693561",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5693561"
}
]
},
{
"id": "R-HSA-5693564",
"name": "Association of RAD51 with RAD52:DNA double-strand break ends",
"equation": "",
"summary": "RAD52 can simultaneously interact with RAD51 and RPA. The interaction with RAD51 may inhibit the formation of the invading RAD51 filament by sequestering RAD51 from RPA, thus promoting single strand annealing (SSA) instead of homologous recombination (Chen et al. 1999, Stark et al. 2004, Singleton et al. 2002, Mansour et al. 2008). The interaction of RAD51 and RAD52 is promoted by ABL1-mediated phosphorylation of both RAD51 and RAD52 (Chen et al. 1999, Van Dyck et al. 1999), which also increases RAD52 affinity for DNA (Honda et al. 2011).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5693564",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5693564"
}
]
},
{
"id": "R-HSA-5693580",
"name": "Association of RAD52 with the RPA complex at resected DNA DSBs",
"equation": "",
"summary": "RAD52 heptamers bind 3' overhanging ssDNA at resected DNA double-strand breaks (DSBs) by simultaneously interacting with the DNA and the RPA complex. The conformation of the RAD52-ssDNA complex is thought to place the ssDNA on an exposed surface of the ring, in a configuration that may promote the DNA-DNA annealing of complementary DNA strands (Parsons et al. 2000). The interaction with RPA is necessary for RAD52-mediated homology driven repair (Park et al. 1996, Jackson et al. 2002). Phosphorylation of RAD52 at tyrosine residue Y104 by ABL1 in response to ATM signaling increases the affinity of RAD52 for DNA (Kitao et al. 2002, Cramer et al. 2008, Honda et al. 2011). Long range resection, which results in the activation of ATR/CHEK1 signaling, is needed for RAD52-mediated single strand annealing (SSA). RAD52 function may be promoted by a direct interaction with WRN helicase which participates in long-range resection of DNA DSBs (Baynton et al. 2003).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-5693580",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5693580"
}
]
},
{
"id": "R-HSA-6799332",
"name": "ATR phosphorylates TP53",
"equation": "",
"summary": "ATR, bound to DNA damage sites, phosphorylates TP53 (p53) at serine residue S15. S15 phosphorylation stabilizes TP53 by inhibiting the binding of TP53 to the ubiquitin ligase MDM2 (Tibbetts et al. 1999, Lakin et al. 1999).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-6799332",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-6799332"
}
]
},
{
"id": "R-HSA-9709571",
"name": "BRCA2 mutants with BRC defects or a defect in the C-terminal RAD51 binding site do not bind RAD51",
"equation": "",
"summary": "BRCA2 contains 8 BRC repeats in its middle region, which are involved in binding to RAD51 at resected DNA double-strand breaks (DSBs) (Bork et al. 1996, Wong et al. 1997, Venkitaraman 2002). Some BRCA2 missense mutations reported in cancer have been shown to impair BRCA2 binding to RAD51.
BRCA2 G1529R mutant, involved in familial breast cancer, has a missense mutation that affects the fourth BRC repeat of BRCA2 (BRC4). The BRC4 construct which harbors the G1529R substitution shows 20-fold reduced binding to RAD51 relative to the wild type BRC4 (Chen et al. 1999). CHEK1 phosphorylation sites are preserved in BRCA2 G1529R mutant, but the phosphorylation is not shown as it has not been tested.
BRCA2 mutant BRCA2 G1529E is annotated as candidate mutant for the loss of RAD51 binding as it has been reported in cancer, is predicted to be pathogenic and involves the same amino acid residue as the functionally characterized BRCA2 G1529R mutant.
The C-terminal RAD51 interaction site, TR2, binds to RAD51 filaments and protects them from disassembly (Davies et al. 2007). TR2 is essential for the replication fork stabilization function of BRCA2 but dispensable for homology-directed repair (Schlacher et al. 2011). BRCA2 S3291A mutant, generated by directed mutagenesis, is unable to bind to RAD51. This mutant has not been reported in cancer but is documented as a BRCA2 allele in the ClinGen Allele Registry (Pawliczek et al. 2018).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P38398-1",
"Q13315-1",
"Q92993-1",
"Q13535-1",
"P54132-1",
"P49959-1",
"Q9UQ84-1",
"Q13472-1",
"Q99728-1",
"Q99708-1",
"Q9BX63-1",
"Q92878-1",
"O60671-1",
"Q99638-1"
],
"evidence": [
{
"id": "R-HSA-9709571",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9709571"
}
]
}
],
"reaction_participants": [
{
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"participant_name": "p-T916,S945-CLSPN [nucleoplasm]",
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{
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{
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{
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"participant_name": "RHNO1 [nucleoplasm]",
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},
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