Suppression of genomic instability by replicative senescence and crisis

Abstract

Replicative senescence and crisis are proliferative barriers, activated as a response to telomere shortening and the resulting loss of chromosome end protection. Cells that enter replicative senescence usually maintain a stable genome, while bypass of senescence through loss of p53 and Rb pathways leads to the accumulation of chromosomal end-to-end fusions. Such fusions activate the spindle assembly checkpoint and a cell death program referred to as replicative crisis. Crisis is remarkably effective in removing cells that have bypassed senescence from the population; however, rarely cells escape, which then are thought to progress to a malignant phenotype. These observations suggest that crisis is the final barrier against cancer formation, yet it is still poorly understood how cells die in crisis, in which molecular cascades play a role in escape from crisis, and whether cells that emerge from crisis can be considered as cancer cells, pinpointing that a better understanding of these pathways is critical to target cancer formation in its earliest stages.