DNA exonucleases DCLRE1A (SNM1A) and DCLRE1B (SNM1B) likely function redundantly in ICL repair. Similar to FAN1, they are able to digest the DNA past the ICL, thereby unhooking one of the DNA strands (Wang et al. 2011, Sengerova et al. 2012). Monoubiquitination of the PCNA subunit of the stalled replicative polymerase complex by RAD18 may provide the docking site for DCLRE1A (or DCLRE1B) (Yang et al. 2010). In addition, PIAS1 may facilitate loading of DCLRE1A (or DCLRE1B) to ICL sites (Ishiai et al. 2004).", "cellular_location": "nucleoplasm", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "Q6PJP8-1", "Q92889-1", "Q9NW38-1", "Q9BQ83-1", "Q96AY2-1", "Q96NY9-1", "Q9H816-1", "A4GXA9-1", "Q8IYD8-1", "Q9Y2M0-1", "O94782-1" ], "evidence": [ { "id": "R-HSA-6785732", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-6785732" } ] }, { "id": "R-HSA-6785986", "name": "DNA nucleases unhook the interstrand crosslink (ICL)", "equation": "", "summary": "Unhooking of interstrand crosslinks (ICLs) from damaged DNA (ICL-DNA) involves coordinated action of several DNA nucleases: FAN1, DCLRE1A or DCLRE1B, the complex of ERCC1 and ERCC4 (XPF), and the complex of SLX4 (FANCP), SLX1A, MUS81 and EME1 or EME2. These DNA nucleases incise ICL-DNA at both sides of the ICL, thus removing the covalent bond between the two DNA strands. The exact sequence of incision steps has not been determined and it is possible that some of the implicated nucleases act in a redundant manner.
FAN1 exhibits 5'->3' endonuclease activity, as well as 5'->3' exonuclease activity, with a preference for 5' flaps and branched DNA structures (Smogorzewska et al. 2010, Kratz et al. 2010, MacKay et al. 2010, Liu et al. 2010). The FAN1 head-to-tail homodimer recognizes the lesion, orients and unwinds the 5' flap (Zhao et al. 2014). FAN1 requires a 5' terminal phosphate anchor and successively cleaves the DNA at every third nucleotide (Wang et al. 2014). This suggests that an incision 5' to the ICL precedes the action of FAN1.
ERCC4 (XPF) in complex with ERCC1 may perform the first endonucleolytic incision 5' to the ICL (Wang et al. 2011), while MUS81 in complex with EME1 or EME2 may act as a backup endonuclease. DCLRE1A (SNM1A) exhibits a 5'->3' exonuclease activity and can digest past the ICL, thereby unhooking it from one DNA strand after the ERCC1:ERCC4 complex does the initial incision 5' to the ICL (Wang et al. 2011). DCLRE1A functions redundantly with DCLRE1B (SNM1B) in ICL repair (Ishiai et al. 2004, Sangerova et al. 2012).", "cellular_location": "nucleoplasm", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "Q6PJP8-1", "Q92889-1", "Q9NW38-1", "Q9BQ83-1", "Q96AY2-1", "Q96NY9-1", "Q9H816-1", "A4GXA9-1", "Q8IYD8-1", "Q9Y2M0-1" ], "evidence": [ { "id": "R-HSA-6785986", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-6785986" } ] } ], "reaction_participants": [], "reaction_enzymes": [ { "uniprot_ac": "A4GXA9", "gene_name": "EME2", "activity": [ { "ec_number": "3.1.22.-", "activity": "", "evidence": [ { "id": "A4GXA9", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/A4GXA9" } ] } ] }, { "uniprot_ac": "O94782", "gene_name": "USP1", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "O94782", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O94782" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "O94782", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O94782" } ] } ] }, { "uniprot_ac": "P38398", "gene_name": "BRCA1", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "P38398", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P38398" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "P38398", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P38398" } ] } ] }, { "uniprot_ac": "P49959", "gene_name": "MRE11", "activity": [ { "ec_number": "3.1.-.-", "activity": "", "evidence": [ { "id": "P49959", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P49959" } ] } ] }, { "uniprot_ac": "P54132", "gene_name": "BLM", "activity": [ { "ec_number": "3.6.4.12", "activity": "ATP + H2O = ADP + H(+) + phosphate.", "evidence": [ { "id": "P54132", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P54132" } ] }, { "ec_number": "3.6.4.12", "activity": "", "evidence": [ { "id": "P54132", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P54132" } ] } ] }, { "uniprot_ac": "Q13315", "gene_name": "ATM", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q13315", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13315" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "Q13315", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13315" } ] } ] }, { "uniprot_ac": "Q13472", "gene_name": "TOP3A", "activity": [ { "ec_number": "5.6.2.1", "activity": "ATP-independent breakage of single-stranded DNA, followed by passage and rejoining.", "evidence": [ { "id": "Q13472", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13472" } ] }, { "ec_number": "5.6.2.1", "activity": "", "evidence": [ { "id": "Q13472", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13472" } ] } ] }, { "uniprot_ac": "Q17RS7", "gene_name": "GEN1", "activity": [ { "ec_number": "3.1.-.-", "activity": "", "evidence": [ { "id": "Q17RS7", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q17RS7" } ] } ] }, { "uniprot_ac": "Q6PJP8", "gene_name": "DCLRE1A", "activity": [ { "ec_number": "3.5.2.6", "activity": "a beta-lactam + H2O = a substituted beta-amino acid.", "evidence": [ { "id": "Q6PJP8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q6PJP8" } ] } ] }, { "uniprot_ac": "Q8IYD8", "gene_name": "FANCM", "activity": [ { "ec_number": "3.6.4.13", "activity": "ATP + H2O = ADP + H(+) + phosphate.", "evidence": [ { "id": "Q8IYD8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8IYD8" } ] }, { "ec_number": "3.6.4.13", "activity": "", "evidence": [ { "id": "Q8IYD8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8IYD8" } ] } ] }, { "uniprot_ac": "Q92878", "gene_name": "RAD50", "activity": [ { "ec_number": "3.6.-.-", "activity": "", "evidence": [ { "id": "Q92878", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q92878" } ] } ] }, { "uniprot_ac": "Q92889", "gene_name": "ERCC4", "activity": [ { "ec_number": "3.1.-.-", "activity": "", "evidence": [ { "id": "Q92889", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q92889" } ] } ] }, { "uniprot_ac": "Q92993", "gene_name": "KAT5", "activity": [ { "ec_number": "2.3.1.48", "activity": "acetyl-CoA + L-lysyl-[histone] = CoA + H(+) + N(6)-acetyl-L-lysyl-[histone].", "evidence": [ { "id": "Q92993", "database": 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"https://www.uniprot.org/uniprot/Q99708" } ] } ] }, { "uniprot_ac": "Q99728", "gene_name": "BARD1", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q99728", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q99728" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q99728", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q99728" } ] } ] }, { "uniprot_ac": "Q9BQ83", "gene_name": "SLX1A", "activity": [ { "ec_number": "3.1.-.-", "activity": "", "evidence": [ { "id": "Q9BQ83", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9BQ83" } ] } ] }, { "uniprot_ac": "Q9BX63", "gene_name": "BRIP1", "activity": [ { "ec_number": "3.6.4.13", "activity": "ATP + H2O = ADP + H(+) + phosphate.", "evidence": [ { "id": 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