Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 3, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI140105
Keywords
-
Categories
Funding
- STARS21
- Terry Fox Foundation
- Princess Margaret Cancer Foundation
- Department of Medical Biophysics
- Government of Ontario
- Canadian Institutes of Health Research (CIHR) [FDN 143214]
- Canadian Cancer Society [705367, 706439]
- Worldwide Cancer Research [110215]
- CIHR [PJT403267, FDN-159913, FDN154328, MOP119289]
- Generalitat de Catalunya AGAUR [2017-4492014]
- CERCA Programme
- Spanish Ministry of Health ISCIII FIS grants [PI15/00854, PI18/01029]
- European Commission, Fondo Europeo de Desarrollo Regional (FEDER), A way to make Europe
- Genome Canada
- Genome Quebec operating grant
- Cancer Research UK [C12292/A20861, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]
- European Community [223175 (HEALTH-F2-2009-223175)]
- NIH [CA128978]
- Post-Cancer GWAS Initiative (GAME-ON Initiative) [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- US Department of Defense [W81XWH-10-1-0341]
- CIHR for the CIHR Team in Familial Risks of Breast Cancer [CRN-87521]
- Ministry of Economic Development, Innovation and Export Trade, Quebec, Canada [PSR-SIIRI-701]
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- Government of Canada (through Genome Canada)
- CIHR
- Ministry of Economy, Science and Innovation (through Genome Quebec)
- Quebec Breast Cancer Foundation
Ask authors/readers for more resources
Germline mutations in BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancer, while the loss of RNF168 can protect Brca1-mutant mice against mammary tumorigenesis. Studies have shown that RNF168 deficiency leads to accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, causing cell death.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available