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

Homo sapiens

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), Adapted from Pino et al. Proteins on this pathway have targeted assays available via the [ CPTAC Assay Portal]


Kristina Hanspers


last edited

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Homo sapiens




Pathway Ontology

cell cycle pathway, mitotic


Label Type Compact URI Comment
MAD1L1 GeneProduct ensembl:ENSG00000002822
ESPL1 GeneProduct ensembl:ENSG00000135476
CDC20 GeneProduct ensembl:ENSG00000117399
SMC1A GeneProduct ensembl:ENSG00000072501
MAD2L1 GeneProduct ensembl:ENSG00000164109
BUB1 GeneProduct ensembl:ENSG00000169679
BUB1B GeneProduct ensembl:ENSG00000156970
BUB3 GeneProduct ensembl:ENSG00000154473
CENPE GeneProduct ensembl:ENSG00000138778
APC GeneProduct ncbigene:324
PTTG1 GeneProduct ensembl:ENSG00000164611
ESPL1 GeneProduct ensembl:ENSG00000135476
PTTG1 GeneProduct ensembl:ENSG00000164611
SMC3 GeneProduct ensembl:ENSG00000108055
RAD21 GeneProduct ensembl:ENSG00000164754
STAG1 GeneProduct ensembl:ENSG00000118007
ESPL1 GeneProduct ensembl:ENSG00000135476


  1. The chromosomal instability pathway in colon cancer. Pino MS, Chung DC. Gastroenterology. 2010 Jun;138(6):2059–72. PubMed Europe PMC Scholia