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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Veröffentlicht in:	The EMBO journal Jg. 38; H. 21; S. e102361 - n/a
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 04.10.2019 Springer Nature B.V John Wiley and Sons Inc
Schlagworte:	Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Ataxin Ataxin 3 Ataxin-3 - genetics Ataxin-3 - metabolism BRCA2 protein Breast cancer Cancer Cell Survival Chromatin Chromatin - genetics Damage Deactivation Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA damage DNA double‐strand break repair DNA Repair DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism E3 ubiquitin ligase RNF8 EMBO13 EMBO31 genome stability Genomes Genomic Instability Genotoxicity HEK293 Cells HeLa Cells Homeostasis Homologous recombination Homology Humans Inactivation Ionizing radiation Medical prognosis Metastases Non-homologous end joining Nuclear Proteins - genetics Nuclear Proteins - metabolism p97/VCP ATPase Physiology Proteasome Endopeptidase Complex - metabolism Proteasomes Proteolysis Recruitment Repair Signal Transduction Tumors Ubiquitin Ubiquitin - metabolism Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination genome stability DNA double‐strand break repair Ataxin 3 p97/VCP ATPase E3 ubiquitin ligase RNF8 DNA double-strand break repair
ISSN:	0261-4189, 1460-2075, 1460-2075
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Zusammenfassung:	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. Synopsis The RNF8 ubiquitin ligase is a key mediator of the ubiquitin‐mediated DNA damage response and regulator of double strand break repair pathway choice. Here, these roles are shown to depend on homeostatic regulation of RNF8 by the ubiquitin‐dependent segregase p97/VCP and the deubiquitinase Ataxin 3 (ATX3). A p97‐ATX3 complex maintains proteasome‐dependent RNF8 homeostasis under physiological condition. The p97‐ATX3 complex extracts RNF8 from chromatin after its recruitment to DNA damage sites. p97‐ATX3‐mediated RNF8 extraction promotes timely RNF168 recruitment and utilization of non‐homologous end joining (NHEJ) repair. Inactivation of the p97‐ATX3 complex hyper‐sensitizes BRCA2/homologous recombination‐deficient cells to ionizing radiation. Graphical Abstract Chromatin extraction of RNF8 by the ubiquitin‐dependent segregase p97/VCP and the deubiquitinase ATX3 emerges as a key mechanism for balancing DNA repair pathway choice.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.2019102361