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. image Loss of the DNA mismatch recognition factor MSH 2 suppresses interstrand crosslink ( ICL ) sensitivity in cells with specific defects in the BRCA 1/Fanconi anemia pathway, suggesting that pathway crosstalk is important to prevent toxic DNA damage responses. ICL sensitivity, DNA damage response activation, and chromosomal abnormalities in cells lacking FANCJ – MLH 1 interaction are suppressed by MSH 2 depletion. MSH 2 depletion increases ICL resistance through R ad18‐dependent translesion synthesis pathways. MSH 2 loss in cells lacking the FANCJ – MLH 1 interaction facilitates DNA replication restart. MSH 2 loss rescues ICL resistance in FANCJ ‐, BRCA 1‐, and FANCD 2‐deficient cells, but not FANCA ‐deficient cells. Msh2 deletion suppresses ICL sensitivity, chromosomal aberrations, and DNA damage response activation also in F ancd2‐deficient primary mouse cells.