Genetic Separation of BRCA1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities

Authors

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, Thomas Jefferson UniversityFollow
Gaorav P. Gupta
Joseph R. Testa
Neil Johnson

Document Type

Article

Publication Date

11-24-2023

Comments

This article is the author's final published version in Nature Communications, Volume 14, Issue 1, 2023, Article number 7714.

The published version is available at https://doi.org/10.1038/s41467-023-43446-1. Copyright © The Author(s) 2023.

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.

Recommended Citation

Krais, John J.; Glass, David J.; Chudoba, Ilse; Wang, Yifan; Feng, Wanjuan; Simpson, Dennis; Patel, Pooja; Liu, Zemin; Neumann-Domer, Ryan; Betsch, Robert G.; Bernhardy, Andrea J.; Bradbury, Alice M.; Conger, Jason; Yueh, Wei-Ting; Nacson, Joseph; Pomerantz, Richard T.; Gupta, Gaorav P.; Testa, Joseph R.; and Johnson, Neil, "Genetic Separation of BRCA1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities" (2023). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 247.
https://jdc.jefferson.edu/bmpfp/247

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

38001070

Language

English