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Crosstalk between BRCA ‐ F anconi anemia and mismatch repair pathways prevents MSH 2‐dependent aberrant DNA damage responses
Author(s) -
Peng Min,
Xie Jenny,
Ucher Anna,
Stavnezer Janet,
Cantor Sharon B
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201387530
Subject(s) - fancd2 , msh2 , fanconi anemia , fanca , biology , dna mismatch repair , dna damage , dna repair , crosstalk , microbiology and biotechnology , homologous recombination , mlh1 , cancer research , genetics , dna , physics , optics
Several proteins in the BRCA ‐ F anconi anemia ( FA ) pathway, such as FANCJ , BRCA 1, and FANCD 2, 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 ( ICL s), although MMR proteins bind ICL s 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 MLH 1 is suppressed by depletion of the upstream mismatch recognition factor MSH 2. MSH 2 depletion suppresses an aberrant DNA damage response, restores cell cycle progression, and promotes ICL resistance through a R ad18‐dependent mechanism. MSH 2 depletion also suppresses ICL sensitivity in cells deficient for BRCA 1 or FANCD 2, but not FANCA . Rescue by M sh2 loss was confirmed in F ancd2‐null primary mouse cells. Thus, we propose that regulation of MSH 2‐dependent DNA damage response underlies the importance of interactions between BRCA ‐ FA and MMR pathways.