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

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 slip-page of cells into G1 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 deg-radation. Here, we report that hyperphosphorylated HIPK2 kinase accumulates in mitotic cells and phosphory-lates the Rett syndrome protein MeCP2 at Ser92, a regulation that is counteracted by CDC14B phosphatase. MeCP2S92 phosphorylation leads to the enhanced translation of cyclin B1, which is important for cells with per-sistent SAC activation to counteract the proteolytic decline of cyclin B1 and therefore to suspend mitotic slip-page. 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.

Automated summary

Mitotic perturbations activate the spindle assembly checkpoint (SAC), causing cells to stay in prometaphase with high CDK1 activity. Prolonged mitotic arrest is bypassed by gradual cyclin B decline followed by slip-page of cells into G1 without chromosome segregation. HIPK2 kinase accumulates in mitotic cells and phosphorylates the Rett syndrome protein MeCP2 at Ser92, leading to enhanced translation of cyclin B1, which helps counteract the proteolytic decline of cyclin B1 and suspend mitotic slip-page. The HIPK2/CDC14B-MeCP2 axis functions as an enhancer of the SAC-induced mitotic block.