Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting

George E. Ronson, Katarzyna Starowicz, Elizabeth J. Anthony, Ann Liza Piberger, Lucy C. Clarke, Alexander J. Garvin, Andrew D. Beggs, Celina M. Whalley, Matthew J. Edmonds, James F. J. Beesley and Joanna R. Morris ()
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George E. Ronson: University of Birmingham
Katarzyna Starowicz: University of Birmingham
Elizabeth J. Anthony: University of Birmingham
Ann Liza Piberger: University of Birmingham
Lucy C. Clarke: University of Birmingham
Alexander J. Garvin: University of Birmingham
Andrew D. Beggs: University of Birmingham
Celina M. Whalley: University of Birmingham
Matthew J. Edmonds: University of Birmingham
James F. J. Beesley: University of Birmingham
Joanna R. Morris: University of Birmingham

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes. We show that in the absence of Polθ, RAD52 accumulations suppress ssDNA gap-filling in G2/M and encourage MRE11 nuclease accumulation. In contrast, the survival of BRCA1-deficient cells treated with Polθ inhibitor are not restored by RAD52 suppression, and ssDNA gap-filling is prevented by the chemically inhibited polymerase itself. These data define an additional role for Polθ, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Polθ loss, and indicate genotype-dependent Polθ inhibitor mechanisms.

Date: 2023
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DOI: 10.1038/s41467-023-43677-2

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