RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells

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
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. (ORCID Profile 0000-0001-8690-5828)
Arrowsmith, Cheryl
Raught, Brian
Pujana, Miguel A.
Mekhail, Karim
Stewart, Grant S.
Hakem, Anne
Hakem, Razqallah

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