Suppression of DNA Polymerase β Activity Is Synthetically Lethal in BRCA1-Deficient Cells

Shelby C. Yuhas, Alok Mishra, Theodore L. Deweese, Marc M. Greenberg

Research output: Contribution to journalArticlepeer-review


People whose cells express mutated forms of the BRCA1 tumor suppressor are at a higher risk for developing cancer. BRCA1-deficient cells are defective in DNA double-strand break repair. The inhibition of poly(ADP-ribose) polymerase 1 in such cells is a synthetically lethal, cytotoxic effect that has been exploited to produce anticancer drugs such as Olaparib. However, alternative synthetic lethal approaches are necessary. We report that DNA polymerase β (Pol β) forms a synthetically lethal interaction with BRCA1. The SiRNA knockdown of Pol β or the treatment with a Pol β pro-inhibitor (pro-1) is cytotoxic in BRCA1-deficient ovarian cancer cells. BRCA1-complemented cells are significantly less susceptible to either treatment. pro-1 is also toxic to BRCA1-deficient breast cancer cells, and its toxicity in BRCA1-deficient cells is comparable to that of Olaparib. These experiments establish Pol β as a synthetically lethal target within BRCA1-deficient cells and a potentially useful one for treating cancer.

Original languageEnglish (US)
Pages (from-to)1339-1343
Number of pages5
JournalACS chemical biology
Issue number8
StatePublished - Aug 20 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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