| Title: |
RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells |
| 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; Arrowsmith, Cheryl; Raught, Brian; Pujana, Miguel A; Mekhail, Karim; Stewart, Grant S; Hakem, Anne; Hakem, Razqallah |
| Contributors: |
Canadian Institute of Health Research; Canadian Cancer Society; Worldwide Cancer Research; Carlos III Institute of Health; Generalitat de Catalunya SGR; CERCA; Quebec Breast Cancer Foundation; Cancer Research UK programme; Princess Margaret Cancer Foundation; Hold’Em for Life Foundation; Strategic Training in Transdisciplinary Radiation Science for the 21st Century; Princess Margaret Cancer Foundation and CIHR fellowship; University of Birmingham; Natural Sciences and Engineering Research Council of Canada; Structural Genomics Consortium; Ontario Genomics Institute |
| Source: |
Nucleic Acids Research ; volume 51, issue 19, page 10484-10505 ; ISSN 0305-1048 1362-4962 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/nar/gkad733 |
| Availability: |
https://doi.org/10.1093/nar/gkad733; https://academic.oup.com/nar/article-pdf/51/19/10484/52581832/gkad733.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.6F12233D |
| Database: |
BASE |