Department of Cancer Biology; Department of Microbiology and Physiological Systems
Adaptor Proteins, Signal Transducing; Animals; BRCA1 Protein; Basic-Leucine Zipper Transcription Factors; Cell Line; Chromosome Aberrations; *DNA Damage; *DNA Mismatch Repair; DNA Replication; DNA-Binding Proteins; Fanconi Anemia Complementation Group A Protein; Fanconi Anemia Complementation Group D2 Protein; Fanconi Anemia Complementation Group Proteins; Humans; Mice; Mice, Mutant Strains; Mitomycin; MutS Homolog 2 Protein; Nuclear Proteins
Biochemistry | Cancer Biology | Genetics | Molecular Genetics | Neoplasms
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.
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Citation: EMBO J. 2014 Aug 1;33(15):1698-712. doi: 10.15252/embj.201387530. Epub 2014 Jun 25. Link to article on publisher's site
Fanconi anemia, FANCJ, mismatch repair, MLH1, replication stress
The EMBO journal
Peng, Min; Xie, Jenny X.; Ucher, Anna J.; Stavnezer, Janet; and Cantor, Sharon B., "Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses" (2014). University of Massachusetts Medical School Faculty Publications. 691.
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