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RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors.

Accepted version
Peer-reviewed

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Authors

Patel, Parasvi S 
Abraham, Karan Joshua 
Guturi, Kiran Kumar Naidu 
Halaby, Marie-Jo 
Khan, Zahra 

Abstract

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brca1-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop-prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability.

Description

Keywords

Breast cancer, Cell Biology, Molecular genetics, Mouse models, Oncology, Animals, BRCA1 Protein, BRCA2 Protein, DNA, Neoplasm, Female, Genetic Loci, Genomic Instability, Humans, Mammary Neoplasms, Animal, Mice, Mice, Knockout, Ovarian Neoplasms, Ubiquitin-Protein Ligases

Journal Title

J Clin Invest

Conference Name

Journal ISSN

0021-9738
1558-8238

Volume Title

131

Publisher

American Society for Clinical Investigation

Rights

All rights reserved
Sponsorship
National Cancer Institute (U19CA148537)
European Commission (223175)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
Cancer Research UK (20861)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research Uk (None)
Cancer Research UK (16565)