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The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8

The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper‐accumulation is tumour‐promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regu...

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Autores principales: Singh, Abhay Narayan, Oehler, Judith, Torrecilla, Ignacio, Kilgas, Susan, Li, Shudong, Vaz, Bruno, Guérillon, Claire, Fielden, John, Hernandez‐Carralero, Esperanza, Cabrera, Elisa, Tullis, Iain DC, Meerang, Mayura, Barber, Paul R, Freire, Raimundo, Parsons, Jason, Vojnovic, Borivoj, Kiltie, Anne E, Mailand, Niels, Ramadan, Kristijan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826192/
https://www.ncbi.nlm.nih.gov/pubmed/31613024
http://dx.doi.org/10.15252/embj.2019102361
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author Singh, Abhay Narayan
Oehler, Judith
Torrecilla, Ignacio
Kilgas, Susan
Li, Shudong
Vaz, Bruno
Guérillon, Claire
Fielden, John
Hernandez‐Carralero, Esperanza
Cabrera, Elisa
Tullis, Iain DC
Meerang, Mayura
Barber, Paul R
Freire, Raimundo
Parsons, Jason
Vojnovic, Borivoj
Kiltie, Anne E
Mailand, Niels
Ramadan, Kristijan
author_facet Singh, Abhay Narayan
Oehler, Judith
Torrecilla, Ignacio
Kilgas, Susan
Li, Shudong
Vaz, Bruno
Guérillon, Claire
Fielden, John
Hernandez‐Carralero, Esperanza
Cabrera, Elisa
Tullis, Iain DC
Meerang, Mayura
Barber, Paul R
Freire, Raimundo
Parsons, Jason
Vojnovic, Borivoj
Kiltie, Anne E
Mailand, Niels
Ramadan, Kristijan
author_sort Singh, Abhay Narayan
collection PubMed
description The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper‐accumulation is tumour‐promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regulating RNF8 homeostasis to preserve genome stability. Here, we identify the cellular machinery, composed of the p97/VCP ubiquitin‐dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a physical and functional complex with RNF8 to regulate its proteasome‐dependent homeostasis under physiological conditions. Under genotoxic stress, when RNF8 is rapidly recruited to sites of DNA lesions, the p97–ATX3 machinery stimulates the extraction of RNF8 from chromatin to balance DNA repair pathway choice and promote cell survival after ionising radiation (IR). Inactivation of the p97–ATX3 complex affects the non‐homologous end joining DNA repair pathway and hypersensitises human cancer cells to IR. We propose that the p97–ATX3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions and that targeting ATX3 may be a promising strategy to radio‐sensitise BRCA‐deficient cancers.
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spelling pubmed-68261922019-11-07 The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8 Singh, Abhay Narayan Oehler, Judith Torrecilla, Ignacio Kilgas, Susan Li, Shudong Vaz, Bruno Guérillon, Claire Fielden, John Hernandez‐Carralero, Esperanza Cabrera, Elisa Tullis, Iain DC Meerang, Mayura Barber, Paul R Freire, Raimundo Parsons, Jason Vojnovic, Borivoj Kiltie, Anne E Mailand, Niels Ramadan, Kristijan EMBO J Articles The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper‐accumulation is tumour‐promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regulating RNF8 homeostasis to preserve genome stability. Here, we identify the cellular machinery, composed of the p97/VCP ubiquitin‐dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a physical and functional complex with RNF8 to regulate its proteasome‐dependent homeostasis under physiological conditions. Under genotoxic stress, when RNF8 is rapidly recruited to sites of DNA lesions, the p97–ATX3 machinery stimulates the extraction of RNF8 from chromatin to balance DNA repair pathway choice and promote cell survival after ionising radiation (IR). Inactivation of the p97–ATX3 complex affects the non‐homologous end joining DNA repair pathway and hypersensitises human cancer cells to IR. We propose that the p97–ATX3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions and that targeting ATX3 may be a promising strategy to radio‐sensitise BRCA‐deficient cancers. John Wiley and Sons Inc. 2019-10-15 2019-11-04 /pmc/articles/PMC6826192/ /pubmed/31613024 http://dx.doi.org/10.15252/embj.2019102361 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Singh, Abhay Narayan
Oehler, Judith
Torrecilla, Ignacio
Kilgas, Susan
Li, Shudong
Vaz, Bruno
Guérillon, Claire
Fielden, John
Hernandez‐Carralero, Esperanza
Cabrera, Elisa
Tullis, Iain DC
Meerang, Mayura
Barber, Paul R
Freire, Raimundo
Parsons, Jason
Vojnovic, Borivoj
Kiltie, Anne E
Mailand, Niels
Ramadan, Kristijan
The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title_full The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title_fullStr The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title_full_unstemmed The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title_short The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8
title_sort p97–ataxin 3 complex regulates homeostasis of the dna damage response e3 ubiquitin ligase rnf8
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826192/
https://www.ncbi.nlm.nih.gov/pubmed/31613024
http://dx.doi.org/10.15252/embj.2019102361
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