Krishnan, Rehna, Lapierre, Mariah, Gautreau, Brandon, Nixon, Kevin C.J., El Ghamrasni, Samah, Patel, Parasvi S., Hao, Jun, Yerlici, V. Talya, Guturi, Kiran Kumar Naidu, St-Germain, Jonathan, Mateo, Francesca, Saad, Amine, Algouneh, Arash, Earnshaw, Rebecca, Shili, Duan, Seitova, Alma, Miller, Joshua, Khosraviani, Negin, Penn, Adam, Ho, Brandon, Sanchez, Otto, Hande, M. Prakash, Masson, Jean Yves, Brown, Grant W., Alaoui-Jamali, Moulay, Reynolds, John J., Arrowsmith, Cheryl, Raught, Brian, Pujana, Miguel A., Mekhail, Karim, Stewart, Grant S., Hakem, Anne and Hakem, Razqallah (2023). RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells. Nucleic Acids Research, 51 (19), pp. 10484-10505.
Abstract
Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
Publication DOI: | https://doi.org/10.1093/nar/gkad733 |
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Divisions: | College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences Aston University (General) |
Funding Information: | Funding: Canadian Institute of Health Research [FDN-143214 to R.H., FDN-159913 to G.W.B., FDN-388879 to J.Y.M., CIHR-399687 to K.M., MOP119289 to B.R.]; Canadian Cancer Society [705367, 706439 to R.H.]; Worldwide Cancer Research [110215 to R.H.]; Carlos I |
Additional Information: | Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
Uncontrolled Keywords: | Genetics |
Publication ISSN: | 1362-4962 |
Data Access Statement: | The data underlying this article are available in GEO at https://www.ncbi.nlm.nih.gov/geo/, and can be accessed with accession number GSE202723. |
Last Modified: | 30 Oct 2024 08:43 |
Date Deposited: | 10 Jun 2024 15:45 |
Full Text Link: | |
Related URLs: |
https://academi ... 9/10484/7269184
(Publisher URL) http://www.scop ... tnerID=8YFLogxK (Scopus URL) |
PURE Output Type: | Article |
Published Date: | 2023-10-27 |
Published Online Date: | 2023-09-11 |
Accepted Date: | 2023-08-24 |
Authors: |
Krishnan, Rehna
Lapierre, Mariah Gautreau, Brandon Nixon, Kevin C.J. El Ghamrasni, Samah Patel, Parasvi S. Hao, Jun Yerlici, V. Talya Guturi, Kiran Kumar Naidu St-Germain, Jonathan Mateo, Francesca Saad, Amine Algouneh, Arash Earnshaw, Rebecca Shili, Duan Seitova, Alma Miller, Joshua Khosraviani, Negin Penn, Adam Ho, Brandon Sanchez, Otto Hande, M. Prakash Masson, Jean Yves Brown, Grant W. Alaoui-Jamali, Moulay Reynolds, John J. ( 0000-0001-8690-5828) Arrowsmith, Cheryl Raught, Brian Pujana, Miguel A. Mekhail, Karim Stewart, Grant S. Hakem, Anne Hakem, Razqallah |