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RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells by Rehna Krishnan; Mariah Lapierre; Brandon Gautreau; Kevin C J Nixon; Samah El Ghamrasni; Parasvi S Patel; Jun Hao; V Talya Yerlici; Kiran Kumar Naidu Guturi; Jonathan St-Germain; Francesca Mateo; Amine Saad; Arash Algouneh; Rebecca Earnshaw; Duan Shili; Alma Seitova; Joshua Miller; Negin Khosraviani; Adam Penn; Brandon Ho; Otto Sanchez; M Prakash Hande; Jean-Yves Masson; Grant W Brown; Moulay Alaoui-Jamali; John J Reynolds; Cheryl Arrowsmith; Brian Raught; Miguel A Pujana; Karim Mekhail; Grant S Stewart; Anne Hakem; Razqallah Hakem is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## 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.

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Author

Rehna Krishnan; Mariah Lapierre; Brandon Gautreau; Kevin C J Nixon; Samah El Ghamrasni; Parasvi S Patel; Jun Hao; V Talya Yerlici; Kiran Kumar Naidu Guturi; Jonathan St-Germain; Francesca Mateo; Amine Saad; Arash Algouneh; Rebecca Earnshaw; Duan Shili; Alma Seitova; Joshua Miller; Negin Khosraviani; Adam Penn; Brandon Ho; Otto Sanchez; M Prakash Hande; Jean-Yves Masson; Grant W Brown; Moulay Alaoui-Jamali; John J Reynolds; Cheryl Arrowsmith; Brian Raught; Miguel A Pujana; Karim Mekhail; Grant S Stewart; Anne Hakem; Razqallah Hakem

Publisher

Oxford University Press (OUP)

Published

2023

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)