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

TY - JOUR

T1 - The p97-Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8

AU - Singh, Abhay Narayan

AU - Oehler, Judith

AU - Torrecilla, Ignacio

AU - Kilgas, Susan

AU - Li, Shudong

AU - Vaz, Bruno

AU - Guerillon, Claire

AU - Fielden, John

AU - Esperanza Hernandez-Carralero, null

AU - Cabrera, Elisa

AU - Tullis, Iain D. C.

AU - Meerang, Mayura

AU - Barber, Paul R.

AU - Freire, Raimundo

AU - Parsons, Jason

AU - Vojnovic, Borivoj

AU - Kiltie, Anne E.

AU - Mailand, Niels

AU - Ramadan, Kristijan

PY - 2019/10/4

Y1 - 2019/10/4

N2 - 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.

AB - 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.

KW - Ataxin 3

KW - DNA double-strand break repair

KW - E3 ubiquitin ligase RNF8

KW - genome stability

KW - p97

KW - VCP ATPase

U2 - 10.15252/embj.2019102361

DO - 10.15252/embj.2019102361

M3 - Journal article

C2 - 31613024

SN - 0261-4189

VL - 38

JO - E M B O Journal

JF - E M B O Journal

ER -