The p97-Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8.
Adenosine Triphosphatases
/ genetics
Ataxin-3
/ genetics
Cell Survival
Chromatin
/ genetics
DNA Breaks, Double-Stranded
DNA Repair
DNA-Binding Proteins
/ genetics
Genomic Instability
HEK293 Cells
HeLa Cells
Homeostasis
Humans
Nuclear Proteins
/ genetics
Proteasome Endopeptidase Complex
/ metabolism
Proteolysis
Signal Transduction
Ubiquitin
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
Ataxin 3
DNA double-strand break repair
E3 ubiquitin ligase RNF8
genome stability
p97/VCP ATPase
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
04 10 2019
04 10 2019
Historique:
received:
30
04
2019
revised:
16
09
2019
accepted:
19
09
2019
pubmed:
16
10
2019
medline:
7
1
2020
entrez:
16
10
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31613024
doi: 10.15252/embj.2019102361
pmc: PMC6826192
doi:
Substances chimiques
Chromatin
0
DNA-Binding Proteins
0
Nuclear Proteins
0
RNF8 protein, human
0
Ubiquitin
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ataxin-3
EC 3.4.19.12
Proteasome Endopeptidase Complex
EC 3.4.25.1
Adenosine Triphosphatases
EC 3.6.1.-
p97 ATPase
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e102361Subventions
Organisme : Cancer Research UK (CRUK)
ID : C5255/A15935
Pays : International
Organisme : Spanish Ministry of Science and Universities
ID : SAF2016-80626-R
Pays : International
Organisme : Medical Research Council
ID : MR/M000354/1
Pays : United Kingdom
Organisme : Swiss National Science Foundation
ID : 31003A_141197
Pays : Switzerland
Organisme : Kraeftens Bekaempelse (Danish Cancer Society)
ID : R146-RP11394
Pays : International
Organisme : UK Research and Innovation | Medical Research Council (MRC)
ID : MC_EX_MR/K022830/1
Pays : International
Organisme : Medical Research Council
ID : MC_UU_00001/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/K022830/1
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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