Journal Article

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

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

2023

Overview

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. What underlies the synthetic lethality between BRCA1/2 or 53BP1 loss and Polθ loss is unclear. Here, the authors show that RPA-RAD52-MRE11 drive lethality when Polθ is absent in these cells. In BRCA1/2-deficient cells, sensitivity to Polθ inhibition additionally depends on the inhibited protein.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/89 / 14 / 14/63 / 631/337/1427 / 631/337/149 / BRCA1 protein / BRCA1 Protein - metabolism / BRCA2 Protein - genetics / BRCA2 Protein - metabolism / Breast cancer / Cell cycle / DNA polymerase / DNA Polymerase theta / DNA Repair / DNA-directed DNA polymerase / Genotypes / Homologous Recombination / Humanities and Social Sciences / Inhibitors / Lethality / Mre11 nuclease / MRE11 protein / multidisciplinary / Nuclease / Phenotypes / Proteins / Rad52 protein / Science / Science (multidisciplinary) / Sensitivity / Synthetic Lethal Mutations / Tumor Suppressor p53-Binding Protein 1 - metabolism / Yeast