UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit
Open Access
- 11 October 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 11 (11), 1363-1369
- https://doi.org/10.1038/ncb1983
Abstract
The anaphase-promoting complex (APC/C), a ubiquitin ligase regulating mitotic progression, is a target for spindle assembly checkpoint. UBE2S, an ubiquitin-conjugating enzyme, is identified as a novel factor that elongates ubiquitin chains and promotes APC/C substrate degradation following release from the spindle assembly checkpoint. 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.This publication has 32 references indexed in Scilit:
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