TY - JOUR
T1 - RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
AU - Krishnan, Rehna
AU - Lapierre, Mariah
AU - Gautreau, Brandon
AU - Nixon, Kevin C.J.
AU - El Ghamrasni, Samah
AU - Patel, Parasvi S.
AU - Hao, Jun
AU - Yerlici, V. Talya
AU - Guturi, Kiran Kumar Naidu
AU - St-Germain, Jonathan
AU - Mateo, Francesca
AU - Saad, Amine
AU - Algouneh, Arash
AU - Earnshaw, Rebecca
AU - Shili, Duan
AU - Seitova, Alma
AU - Miller, Joshua
AU - Khosraviani, Negin
AU - Penn, Adam
AU - Ho, Brandon
AU - Sanchez, Otto
AU - Hande, M. Prakash
AU - Masson, Jean Yves
AU - Brown, Grant W.
AU - Alaoui-Jamali, Moulay
AU - Reynolds, John J.
AU - Arrowsmith, Cheryl
AU - Raught, Brian
AU - Pujana, Miguel A.
AU - Mekhail, Karim
AU - Stewart, Grant S.
AU - Hakem, Anne
AU - Hakem, Razqallah
N1 - 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 [email protected]
PY - 2023/10/27
Y1 - 2023/10/27
N2 - 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.
AB - 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.
UR - https://academic.oup.com/nar/article/51/19/10484/7269184
UR - http://www.scopus.com/inward/record.url?scp=85175356004&partnerID=8YFLogxK
U2 - 10.1093/nar/gkad733
DO - 10.1093/nar/gkad733
M3 - Article
C2 - 37697435
AN - SCOPUS:85175356004
SN - 0305-1048
VL - 51
SP - 10484
EP - 10505
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 19
ER -