Crosstalk between BRCA ‐ F anconi anemia and mismatch repair pathways prevents MSH 2‐dependent aberrant DNA damage responses

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.