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 mutL homolog 1 (MLH1) as a genetic interactor of BRCA2 whose overexpression 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 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 estrogen as inducing MLH1 expression through estrogen receptor alpha (ER alpha), 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 show how it may contribute to the establishment of BRCA2-deficient breast tumors.

Hu, Xiaoju (author)
Peddibhotla, Vaishnavi (author)
Balamurugan, Kuppusamy (author)
Mitrophanov, Alexander Y. (author)
McKennett, Lois (author)
Kharat, Suhas S. (author)
Sanawar, Rahul (author)
Singh, Vinod Kumar,1983Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology(Swepub:gu)xsinvi (author)
Albaugh, Mary E. (author)
Burkett, Sandra S. (author)
Zhao, Yongmei (author)
Tran, Bao (author)
Malys, Tyler (author)
Sterneck, Esta (author)
De, Subhajyoti (author)
Sharan, Shyam K. (author)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi (creator_code:org_t)

By the author/editor: Sengodan, Sathee ...; Hu, Xiaoju; Peddibhotla, Vai ...; Balamurugan, Kup ...; Mitrophanov, Ale ...; McKennett, Lois; show more...; Kharat, Suhas S.; Sanawar, Rahul; Singh, Vinod Kum ...; Albaugh, Mary E.; Burkett, Sandra ...; Zhao, Yongmei; Tran, Bao; Malys, Tyler; Sterneck, Esta; De, Subhajyoti; Sharan, Shyam K.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Medical Biotechn ...; and Medical Biotechn ...

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