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EMBO J. 2019 Oct 4;38(21):e102361. doi: 10.15252/embj.2019102361. Epub 2019 Oct 15.

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

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Department of Oncology, Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain.
Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain.
Institute of Pharmacology and Toxicology-Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
Universidad Fernando Pessoa Canarias, Santa Maria de Guia, Spain.
Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool, UK.


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.


Ataxin 3; DNA double-strand break repair; E3 ubiquitin ligase RNF8; genome stability; p97/VCP ATPase

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