title: Replication Protein A (RPA) deficiency activates the Fanconi anemia DNA repair pathway.
abstract: The Fanconi anemia (FA) pathway regulates DNA inter-strand crosslink (ICL) repair. Despite our greater understanding of the role of FA in ICL repair, its function in the preventing spontaneous genome instability is not well understood. Here, we show that depletion of replication protein A (RPA) activates the FA pathway. RPA1 deficiency increases chromatin recruitment of FA core complex, leading to FANCD2 monoubiquitination (FANCD2-Ub) and foci formation in the absence of DNA damaging agents. Importantly, ATR depletion, but not ATM, abolished RPA1 depletion-induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub. Interestingly, we found that depletion of hSSB1/2-INTS3, a single-stranded DNA-binding protein complex, induces FANCD2-Ub, like RPA1 depletion. More interestingly, depletion of either RPA1 or INTS3 caused increased accumulation of DNA damage in FA pathway deficient cell lines. Taken together, these results indicate that RPA deficiency induces activation of the FA pathway in an ATR-dependent manner, which may play a role in the genome maintenance.
authors.affiliation: a Department of Pharmacology , Medical Research Center for Gene Regulation, Chonnam National University Medical School , Gwangju , Korea.
authors.forename: Seok-Won
authors.initials: SW
authors.lastname: Jang
authors.affiliation: a Department of Pharmacology , Medical Research Center for Gene Regulation, Chonnam National University Medical School , Gwangju , Korea.
authors.forename: Jin Ki
authors.initials: JK
authors.lastname: Jung
authors.affiliation: a Department of Pharmacology , Medical Research Center for Gene Regulation, Chonnam National University Medical School , Gwangju , Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D005199:Fanconi Anemia / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051716:Replication Protein A / Q000172:deficiency* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; C468783:H2AX protein, human; D006657:Histones; C543505:INTS3 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human
keywords: ATR; FANCD2 monoubiquitination; fanconi anemia; genome instability; replication protein A (RPA)