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| Research article summary (published 9 Oct 2009): |
UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.
Full Abstract
The anaphase-promoting complex (APC/C), a ubiquitin ligase, is the target of the spindle-assembly checkpoint (SAC), and it ubiquitylates protein substrates whose degradation regulates progress through mitosis. The identity of the ubiquitin-conjugating (E2) enzymes that work with the APC/C is unclear. In an RNA interference (RNAi) screen for factors that modify release from drug-induced SAC activation, we identified the E2 enzyme UBE2S as an APC/C auxiliary factor that promotes mitotic exit. UBE2S is dispensable in a normal mitosis, but its depletion prolongs drug-induced mitotic arrest and suppresses mitotic slippage. In vitro, UBE2S elongates ubiquitin chains initiated by the E2 enzymes UBCH10 and UBCH5, enhancing the degradation of APC/C substrates by the proteasome. Indeed, following release from SAC-induced mitotic arrest, UBE2S-depleted cells neither degrade crucial APC/C substrates, nor silence this checkpoint, whereas bypassing the SAC through BUBR1 depletion or Aurora-B inhibition negates the requirement for UBE2S. Thus, UBE2S functions with the APC/C in a two-step mechanism to control substrate ubiquitylation that is essential for mitotic exit after prolonged SAC activation, providing a new model for APC/C function in human cells.
Author information
Author/s: Garnett, Mathew J (MJ); Mansfeld, Jörg (J); Godwin, Colin (C); Matsusaka, Takahiro (T); Wu, Jiahua (J); Russell, Paul (P); Pines, Jonathon (J); Venkitaraman, Ashok R (AR);
Affiliation: University of Cambridge, Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 OXZ, UK.
Grants: (Agency:Canadian Institutes of Health Research) ; (Agency:Cancer Research UK) ; (Agency:Medical Research Council) ; (Agency:Wellcome Trust)
Journal and publication information
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Journal: Nature cell biology (Nat Cell Biol), published in England. (Language: eng)
Reference: 2009-Nov; vol 11 (issue 11) : pp 1363-9
Dates: Created 2009/11/03; Completed 2009/11/16;
PMID: 19820702, status: MEDLINE (last retrieved date: 11/16/2009)
Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.
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Associated Chemicals: Ubiquitin-Conjugating Enzymes (EC 6.3.2.19) ; Ubiquitin-Protein Ligase Complexes (EC 6.3.2.19) ; anaphase-promoting complex (EC 6.3.2.19)Related articles
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