期刊
EMBO JOURNAL
卷 39, 期 12, 页码 -出版社
WILEY
DOI: 10.15252/embj.2019103180
关键词
Cyclin B1; kinetochore corona; MAD; RZZcomplex; spindle assembly checkpoint
资金
- Cancer Research UK [C47320]
- Leng Charitable Trust
- Max Planck Society
- European Research Council (ERC) Advanced Investigator Grant RECEPIANCE [669686]
Cyclin B:CDK1 is the master kinase regulator of mitosis. We show here that, in addition to its kinase functions, mammalian Cyclin B also scaffolds a localised signalling pathway to help preserve genome stability. Cyclin B1 localises to an expanded region of the outer kinetochore, known as the corona, where it scaffolds the spindle assembly checkpoint (SAC) machinery by binding directly toMAD1.In vitroreconstitutions map the key binding interface to a few acidic residues in the N-terminal region ofMAD1, and point mutations in this sequence abolishMAD1 corona localisation and weaken theSAC. Therefore, Cyclin B1 is the long-sought-after scaffold that linksMAD1 to the corona, and this specific pool ofMAD1 is needed to generate a robustSACresponse. Robustness arises because Cyclin B1:MAD1 localisation loses dependence onMPS1 kinase after the corona has been established, ensuring that corona-localisedMAD1 can still be phosphorylated whenMPS1 activity is low. Therefore, this study explains how corona-MAD1 generates a robustSACsignal, and it reveals a scaffolding role for the key mitotic kinase, Cyclin B1:CDK1, which ultimately helps to inhibit its own degradation.
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