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Efficient APC/C substrate degradation in cells undergoing mitotic exit depends on K11 ubiquitin linkages

Mingwei Min, Tycho Mevissen, Maria De Luca, David Komander, Catherine Lindon
doi: https://doi.org/10.1101/016139
Mingwei Min
aUniversity of Cambridge Department of Genetics, Cambridge, UK
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Tycho Mevissen
bMedical Research Council Laboratory of Molecular Biology, Cambridge, UK
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Maria De Luca
aUniversity of Cambridge Department of Genetics, Cambridge, UK
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David Komander
bMedical Research Council Laboratory of Molecular Biology, Cambridge, UK
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Catherine Lindon
aUniversity of Cambridge Department of Genetics, Cambridge, UK
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  • For correspondence: acl34@cam.ac.uk
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Abstract

The ubiquitin proteasome system (UPS) directs programmed destruction of key cellular regulators via post-translational modification of its targets with polyubiquitin chains. These commonly contain Lysine 48 (K48)-directed ubiquitin linkages, but chains containing atypical Lysine 11 (K11) linkages also target substrates to the proteasome, for example to regulate cell cycle progression. A single ubiquitin ligase, the Anaphase Promoting Complex/Cyclosome (APC/C), controls mitotic exit. In higher eukaryotes, the APC/C works with the E2 enzyme UBE2S to assemble K11 linkages in cells released from mitotic arrest, and these are proposed to constitute an improved proteolytic signal during exit from mitosis. We have tested this idea by correlating quantitative measures of in vivo K11-specific ubiquitination of individual substrates, including Aurora kinases, with their degradation kinetics tracked at the single cell level. We report that all anaphase substrates tested by this methodology are stabilized by depletion of K11 linkages via UBE2S knockdown, even if the same substrates are significantly modified with K48-linked polyubiquitin. Specific examination of substrates depending on the APC/C coactivator Cdh1 for their degradation revealed Cdh1-dependent enrichment of K11 chains on these substrates, while other ubiquitin linkages on the same substrates added during mitotic exit were Cdh1-independent. Therefore we show that K11 linkages provide the APC/C with a means to regulate the rate of substrate degradation in a co-activator-specified manner.

APC/C
Anaphase Promoting Complex/Cyclosome
DUB
deubiquitinase
SAC
spindle assembly checkpoint
UPS
ubiquitin-proteasome system
ZM
ZM447439
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Posted March 06, 2015.
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Efficient APC/C substrate degradation in cells undergoing mitotic exit depends on K11 ubiquitin linkages
Mingwei Min, Tycho Mevissen, Maria De Luca, David Komander, Catherine Lindon
bioRxiv 016139; doi: https://doi.org/10.1101/016139
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Efficient APC/C substrate degradation in cells undergoing mitotic exit depends on K11 ubiquitin linkages
Mingwei Min, Tycho Mevissen, Maria De Luca, David Komander, Catherine Lindon
bioRxiv 016139; doi: https://doi.org/10.1101/016139

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