Letter abstract
Nature Cell Biology 11, 1363 - 1369 (2009)
Published online: 11 October 2009 | doi:10.1038/ncb1983
UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit
Mathew J. Garnett1,3,4, Jörg Mansfeld2,3, Colin Godwin1, Takahiro Matsusaka2, Jiahua Wu1, Paul Russell1, Jonathon Pines2 & Ashok R. Venkitaraman1,4
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 mitosis1, 2, 3. 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.
- University of Cambridge, Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 OXZ, UK.
- Wellcome/Cancer Research UK Gurdon Institute and Department of Zoology, Tennis Court Road, Cambridge, CB2 1QN, UK.
- These authors contributed equally to this work.
- Correspondence should be addressed to M.J.G or A.R.V.e-mail: arv22@cam.ac.uk
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