MLH1 Mitigates Replicative Stress and Promotes Synthetic Viability of BRCA2-deficient cells

Authors

• JD Bowling
• CI Aneke
• SE Shahegh
• J Youn
• JM Cuellar-Rodriguez
• A Seyedmousavi

Abstract

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 have identified mismatch-repair gene, MLH1 as a novel genetic interactor of BRCA2 whose over-expression supports the viability of Brca2-null cells. Mechanistically, we show that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrain DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication-fork (RFs) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuates R-loops allowing stable RFs to progress, altogether suppressing the genomic instability. We demonstrate 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 describe that estrogen induces MLH1 expression through estrogen receptor alpha (ER), which may explain why the majority of BRCA2 mutation carriers develop ER positive breast cancer. Taken together, our findings reveal a novel role of MLH1 in relieving replicative stress and how it may contribute to the establishment of BRCA2-deficient breast tumors.

Scientific Focus Area: Genetics and Genomics

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