Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities

John J. Krais (), David J. Glass, Ilse Chudoba, Yifan Wang, Wanjuan Feng, Dennis Simpson, Pooja Patel, Zemin Liu, Ryan Neumann-Domer, Robert G. Betsch, Andrea J. Bernhardy, Alice M. Bradbury, Jason Conger, Wei-Ting Yueh, Joseph Nacson, Richard T. Pomerantz, Gaorav P. Gupta, Joseph R. Testa and Neil Johnson ()
Additional contact information
John J. Krais: Nuclear Dynamics Program, Fox Chase Cancer Center
David J. Glass: Nuclear Dynamics Program, Fox Chase Cancer Center
Ilse Chudoba: MetaSystems Probes, GmbH, Industriestr
Yifan Wang: Nuclear Dynamics Program, Fox Chase Cancer Center
Wanjuan Feng: University of North Carolina
Dennis Simpson: University of North Carolina
Pooja Patel: Nuclear Dynamics Program, Fox Chase Cancer Center
Zemin Liu: Cytogenetics Laboratory, Fox Chase Cancer Center
Ryan Neumann-Domer: Cytogenetics Laboratory, Fox Chase Cancer Center
Robert G. Betsch: Nuclear Dynamics Program, Fox Chase Cancer Center
Andrea J. Bernhardy: Nuclear Dynamics Program, Fox Chase Cancer Center
Alice M. Bradbury: Nuclear Dynamics Program, Fox Chase Cancer Center
Jason Conger: Nuclear Dynamics Program, Fox Chase Cancer Center
Wei-Ting Yueh: Nuclear Dynamics Program, Fox Chase Cancer Center
Joseph Nacson: Nuclear Dynamics Program, Fox Chase Cancer Center
Richard T. Pomerantz: Thomas Jefferson University, Sidney Kimmel Cancer Center, Department of Biochemistry and Molecular Biology
Gaorav P. Gupta: Cancer Control and Prevention Program, Fox Chase Cancer Center
Joseph R. Testa: Cytogenetics Laboratory, Fox Chase Cancer Center
Neil Johnson: Nuclear Dynamics Program, Fox Chase Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq−/− cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were significantly more dependent on Polθ for viability; here, treatment with Polθi elevated RPA foci, which persisted through mitosis. In an isogenic system, BRCA1 null cells were defective, but PALB2 and BRCA2 mutant cells exhibited active resection, and consequently stronger sensitivity to Polθi. Thus, DNA end resection is a critical determinant of Polθi sensitivity in HR-deficient cells, and should be considered when selecting patients for clinical studies.

Date: 2023
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DOI: 10.1038/s41467-023-43446-1

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