The HIPK2/CDC14B-MeCP2 axis enhances the spindle assembly checkpoint block by promoting cyclin B translation

Author:

Partscht Patrick12ORCID,Simon Alexander23ORCID,Chen Nan-Peng1ORCID,Erhardt Sylvia3ORCID,Schiebel Elmar1ORCID

Affiliation:

1. Zentrum für Molekulare Biologie, Universität Heidelberg, DKFZ-ZMBH Allianz, Heidelberg 69120, Germany.

2. Heidelberg Biosciences International Graduate School (HBIGS), Universität Heidelberg, Heidelberg, Germany.

3. Zoological Institute, Karlsruhe Institute of Technology (KIT), Karlsruhe 76131, Germany.

Abstract

Mitotic perturbations activate the spindle assembly checkpoint (SAC) that keeps cells in prometaphase with high CDK1 activity. Prolonged mitotic arrest is eventually bypassed by gradual cyclin B decline followed by slippage of cells into G 1 without chromosome segregation, a process that promotes cell transformation and drug resistance. Hitherto, the cyclin B1 decay is exclusively defined by mechanisms that involve its proteasomal degradation. Here, we report that hyperphosphorylated HIPK2 kinase accumulates in mitotic cells and phosphorylates the Rett syndrome protein MeCP2 at Ser 92 , a regulation that is counteracted by CDC14B phosphatase. MeCP2 S92 phosphorylation leads to the enhanced translation of cyclin B1, which is important for cells with persistent SAC activation to counteract the proteolytic decline of cyclin B1 and therefore to suspend mitotic slippage. Hence, the HIPK2/CDC14B-MeCP2 axis functions as an enhancer of the SAC-induced mitotic block. Collectively, our study revises the prevailing view of how cells confer a sustainable SAC.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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