Chromosome segregation and cancer: cutting through the mystery

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Abstract
Cyclin-dependent kinases (CDKs) are the master regulators of mitosis.They delegate portions of the mitotic programme to other downstream transducers that act directly on various components of mitotic chromosomes, the spindle apparatus and the cytoskeleton. The anaphase-promoting complex/cyclosome (APC/C) normally becomes active at the metaphase–anaphase transition. It triggers the degradation of an anaphase-inhibiting protein, called securin, and cyclin B. Inhibition of the APC/C is one of the principal consequences of spindle-checkpoint activation. In human cells, the formation of a securin–separin complex primes the separin protease for eventual activation in anaphase. Otherwise, securin functions primarily as an inhibitor of the separin protease, which cleaves cohesin bridges, allowing the sister chromatids to move poleward along the mitotic spindle. Genetic instability is a hallmark of virtually all solid tumours. Most cancers are aneuploid and often exhibit cytological abnormalities during mitosis, including abnormal centrosomes, multipolar spindles and lagging chromosomes. More than 100 genes can cause chromosomal instability (CIN) when mutated in yeast cells, many of which have several homologues in humans. These include genes that are involved in chromosome metabolism, spindle assembly and dynamics, cell-cycle regulation and mitotic checkpoint control. Genetic alterations in the mitotic-spindle checkpoint of human cells lead directly to CIN. However, the underlying chromosomal segregration defects can be quite distinct. Cancer cells have numerous defects in their genetic stability mechanisms. The effect of such defects might render most cancers vulnerable to genotoxic challenges that threaten genomic integrity, indicating a possible route to drug discovery.