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.
About The Expert
Parasvi S Patel
Karan Joshua Abraham
Kiran Kumar Naidu Guturi
Marie-Jo Halaby
Zahra Khan
Luis Palomero
Brandon Ho
Shili Duan
Jonathan St-Germain
Arash Algouneh
Francesca Mateo
Samah El Ghamrasni
Haithem Barbour
Daniel R Barnes
Jonathan Beesley
Otto Sanchez
Hal K Berman
Grant W Brown
El Bachir Affar
Georgia Chenevix-Trench
Antonis C Antoniou
Cheryl H Arrowsmith
Brian Raught
Miquel Angel Pujana
Karim Mekhail
Anne Hakem
Razqallah Hakem
References
PubMed