2. Academic Validation
  3. REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps

REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps

  • Mol Cell. 2021 Oct 7;81(19):4008-4025.e7. doi: 10.1016/j.molcel.2021.08.016.
Angelo Taglialatela 1,  Giuseppe Leuzzi 1,  Vincenzo Sannino 2,  Raquel Cuella-Martin 1,  Jen-Wei Huang 1,  Foon Wu-Baer 3,  Richard Baer 3,  Vincenzo Costanzo 2,  Alberto Ciccia 4
Affiliations

Affiliations

  • 1 Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 2 DNA Metabolism Laboratory, IFOM, FIRC Institute for Molecular Oncology, Milan, Italy; Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy.
  • 3 Institute for Cancer Genetics, Department of Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ac3685@cumc.columbia.edu.
PMID: 34508659 DOI: 10.1016/j.molcel.2021.08.016
Abstract

BRCA1/2 mutant tumor cells display an elevated mutation burden, the etiology of which remains unclear. Here, we report that these cells accumulate ssDNA gaps and spontaneous mutations during unperturbed DNA replication due to repriming by the DNA primase-polymerase PRIMPOL. Gap accumulation requires the DNA glycosylase SMUG1 and is exacerbated by depletion of the translesion synthesis (TLS) factor RAD18 or inhibition of the error-prone TLS polymerase complex REV1-Polζ by the small molecule JH-RE-06. JH-RE-06 treatment of BRCA1/2-deficient cells results in reduced mutation rates and PRIMPOL- and SMUG1-dependent loss of viability. Through cellular and animal studies, we demonstrate that JH-RE-06 is preferentially toxic toward HR-deficient Cancer cells. Furthermore, JH-RE-06 remains effective toward PARP Inhibitor (PARPi)-resistant BRCA1 mutant cells and displays additive toxicity with crosslinking agents or PARPi. Collectively, these studies identify a protective and mutagenic role for REV1-Polζ in BRCA1/2 mutant cells and provide the rationale for using REV1-Polζ inhibitors to treat BRCA1/2 mutant tumors.

Keywords

BRCA1 and BRCA2; DNA repriming; PRIMPOL; RAD18; REV1 and Polζ; breast and ovarian cancer; homologous recombination; ssDNA gaps; synthetic lethality; translesion synthesis.

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