title: FANCD2 and REV1 cooperate in the protection of nascent DNA strands in response to replication stress.
abstract: REV1 is a eukaryotic member of the Y-family of DNA polymerases involved in translesion DNA synthesis and genome mutagenesis. Recently, REV1 is also found to function in homologous recombination. However, it remains unclear how REV1 is recruited to the sites where homologous recombination is processed. Here, we report that loss of mammalian REV1 results in a specific defect in replication-associated gene conversion. We found that REV1 is targeted to laser-induced DNA damage stripes in a manner dependent on its ubiquitin-binding motifs, on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1. Expression of a FANCD2-Ub chimeric protein in RAD18-depleted cells enhances REV1 assembly at laser-damaged sites, suggesting that FANCD2-mUb functions downstream of RAD18 to recruit REV1 to DNA breaks. Consistent with this suggestion we found that REV1 and FANCD2 are epistatic with respect to sensitivity to the double-strand break-inducer camptothecin. REV1 enrichment at DNA damage stripes also partially depends on BRCA1 and BRCA2, components of the FANCD2/BRCA supercomplex. Intriguingly, analogous to FANCD2-mUb and BRCA1/BRCA2, REV1 plays an unexpected role in protecting nascent replication tracts from degradation by stabilizing RAD51 filaments. Collectively these data suggest that REV1 plays multiple roles at stalled replication forks in response to replication stress.
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yeran
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Piya
authors.initials: P
authors.lastname: Temviriyanukul
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lingna
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Benjamin P C
authors.initials: BP
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.affiliation: Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330-8262, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Fischhaber
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Errol C
authors.initials: EC
authors.lastname: Friedberg
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China tangtsh@ioz.ac.cn.
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China guocx@big.ac.cn.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
mesh_terms: D002166:Camptothecin / Q000633:toxicity; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology; D004259:DNA-Directed DNA Polymerase; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism / Q000502:physiology*; D005785:Gene Conversion; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs; D013312:Stress, Physiological / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000633:toxicity; D044767:Ubiquitin-Protein Ligases; D000099270:Y-Family DNA Polymerases
chemical_list: D002166:Camptothecin; D004247:DNA; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D059004:Topoisomerase I Inhibitors; D044767:Ubiquitin-Protein Ligases; C485954:RAD18 protein, human; C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases; C496086:Rev1 protein, mouse