2. Academic Validation
  3. POLθ processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells

POLθ processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells

  • Cell Rep. 2022 Nov 15;111716. doi: 10.1016/j.celrep.2022.111716.
Anna Schrempf 1,  Sara Bernardo 2,  Emili A Arasa Verge 2,  Miguel A Ramirez Otero 3,  Jordan Wilson 1,  Dominik Kirchhofer 2,  Gerald Timelthaler 2,  Anna M Ambros 4,  Atilla Kaya 4,  Marcus Wieder 4,  Gerhard F Ecker 4,  Georg E Winter 2,  Vincenzo Costanzo 3,  Joanna I Loizou 5
Affiliations

Affiliations

  • 1 Center for Cancer Research, Comprehensive Cancer Centre, Medical University of Vienna, 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • 2 Center for Cancer Research, Comprehensive Cancer Centre, Medical University of Vienna, 1090 Vienna, Austria.
  • 3 DNA Metabolism Laboratory, IFOM ETS, The AIRC Institute for Molecular Oncology, 20139 Milan, Italy.
  • 4 Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, Austria.
  • 5 Center for Cancer Research, Comprehensive Cancer Centre, Medical University of Vienna, 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address: joanna_loizou@hotmail.com.
PMID: 36400033 DOI: 10.1016/j.celrep.2022.111716
Abstract

Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss is synthetically lethal in Cancer cells bearing breast Cancer susceptibility proteins 1 and 2 (BRCA1/2) mutations. To investigate the basis of this genetic interaction, we utilized a small-molecule inhibitor targeting the POLθ polymerase domain. We found that POLθ processes single-stranded DNA (ssDNA) gaps that emerge in the absence of BRCA1, thus promoting unperturbed replication fork progression and survival of BRCA1 mutant cells. A genome-scale CRISPR-Cas9 knockout screen uncovered suppressors of the functional interaction between POLθ and BRCA1, including NBN, a component of the MRN complex, and cell-cycle regulators such as CDK6. While the MRN complex nucleolytically processes ssDNA gaps, CDK6 promotes cell-cycle progression, thereby exacerbating replication stress, a feature of BRCA1-deficient cells that lack POLθ activity. Thus, ssDNA gap formation, modulated by cell-cycle regulators and MRN complex activity, underlies the synthetic lethality between POLθ and BRCA1, an important insight for clinical trials with POLθ inhibitors.

Keywords

BRCA1; CP: Molecular biology; POLθ; replication stress; ssDNA; synthetic lethality.

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