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

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 signif...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602868/
https://www.ncbi.nlm.nih.gov/pubmed/37697435
http://dx.doi.org/10.1093/nar/gkad733
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author 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
author_facet 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
author_sort Krishnan, Rehna
collection PubMed
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.
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spelling pubmed-106028682023-10-28 RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells 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 Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2023-09-11 /pmc/articles/PMC10602868/ /pubmed/37697435 http://dx.doi.org/10.1093/nar/gkad733 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/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
spellingShingle Genome Integrity, Repair and Replication
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
RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title_full RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title_fullStr RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title_full_unstemmed RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title_short RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells
title_sort rnf8 ubiquitylation of xrn2 facilitates r-loop resolution and restrains genomic instability in brca1 mutant cells
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602868/
https://www.ncbi.nlm.nih.gov/pubmed/37697435
http://dx.doi.org/10.1093/nar/gkad733
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