Mismatch repair protein MLH1 suppresses replicative stress in BRCA2 deficient breast tumors

Loss of BRCA2 (BReast CAncer 2) is lethal for normal cells. Yet, it remains poorly understood how in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we identified mismatch repair gene, MLH1 as a genetic interactor of BRCA2 whose over-expression supports the viability of Brca2-null cells. Mechanistically, we showed that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrained the DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication fork (RF) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuated R-loops, allowing the progression of stable RFs, which suppressed the genomic instability and supported cell viability. We demonstrated the significance of their genetic interaction by the lethality of Brca2-mutant mice and inhibition of Brca2-deficient tumor growth in mice by Mlh1 loss. Furthermore, we described that estrogen induces MLH1 expression through estrogen receptor alpha (ERa), which might explain why the majority of BRCA2 mutation carriers develop ER positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and how it may contribute to the establishment of BRCA2-deficient breast tumors.

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