title: Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses.
abstract: Several proteins in the BRCA-Fanconi anemia (FA) pathway, such as FANCJ, BRCA1, and FANCD2, interact with mismatch repair (MMR) pathway factors, but the significance of this link remains unknown. Unlike the BRCA-FA pathway, the MMR pathway is not essential for cells to survive toxic DNA interstrand crosslinks (ICLs), although MMR proteins bind ICLs and other DNA structures that form at stalled replication forks. We hypothesized that MMR proteins corrupt ICL repair in cells that lack crosstalk between BRCA-FA and MMR pathways. Here, we show that ICL sensitivity of cells lacking the interaction between FANCJ and the MMR protein MLH1 is suppressed by depletion of the upstream mismatch recognition factor MSH2. MSH2 depletion suppresses an aberrant DNA damage response, restores cell cycle progression, and promotes ICL resistance through a Rad18-dependent mechanism. MSH2 depletion also suppresses ICL sensitivity in cells deficient for BRCA1 or FANCD2, but not FANCA. Rescue by Msh2 loss was confirmed in Fancd2-null primary mouse cells. Thus, we propose that regulation of MSH2-dependent DNA damage response underlies the importance of interactions between BRCA-FA and MMR pathways.
authors: Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA.
authors: Min
authors: M
authors: Peng
authors: Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA.
authors: Jenny
authors: J
authors: Xie
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA.
authors: Anna
authors: A
authors: Ucher
authors: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA.
authors: Janet
authors: J
authors: Stavnezer
authors: Department of Cancer Biology, University of Massachusetts Medical School, Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA Sharon.Cantor@umassmed.edu.
authors: Sharon B
authors: SB
authors: Cantor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line / Q000187:drug effects; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000187:drug effects; D053843:DNA Mismatch Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016685:Mitomycin / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C102108:BACH1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C499904:Fancd2 protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C485954:RAD18 protein, human; D016685:Mitomycin; D044767:Ubiquitin-Protein Ligases; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: FANCJ; Fanconi anemia; MLH1; mismatch repair; replication stress