Regulation of sister chromatid separation at the metaphase-anaphase transition (WP4240)

In prometaphase, highly condensed chromosomes establish bipolar attachments to the mitotic spindle. Unattached or mal-orientated chromosomes generate a signal to delay the onset of anaphase until all pairs of sister chromatids are properly aligned on the metaphase plate. This signal is transduced by a relay of spindle-checkpoint proteins, including MAD1, MAD2, BUB1, BUBR1, BUB3 and centrosome protein E (CENPE), which inhibits cell division cycle 20 (CDC20)-mediated activation of an E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/C). Following attachment and alignment of all the chromosomes at metaphase, the checkpoint signal is silenced and APC/C initiates the ubiquitin-dependent degradation of securin and activation of separase. Separase in turn cleaves a multiprotein complex termed cohesin, which creates physical links between sister chromatids to initiate anaphase. This process may be of interest in colorectal cancer, specifically in terms of the chromosome instability phenotype, which could result from defects in pathways that ensure accurate chromosome segregation. Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org. Adapted from Pino et al. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4240 CPTAC Assay Portal]

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