Apoptosis and genomic instability

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Abstract
Genomic instability can be linked to disabled apoptosis, and both phenomena can engage in a positive amplification loop. Genomic instability can disable the apoptotic programme — for example, due to the mutation or deletion of pro-apoptotic genes. The inhibition of apoptosis can favour chromosomal instability (CIN) at several levels. DNA double-strand breaks result in structural CIN when the default pathway that leads to senescence and apoptosis is blocked. Similarly, telomere dysfunction entails rampant structural CIN only when the p53-dependent senescence or apoptosis pathway is disabled. Inactivation of p53 is also permissive for the survival of polyploid cells. Disabling the DNA-structure checkpoint can favour metaphase-associated cell death. Suppression of this 'mitotic catastrophe' by caspase inhibitors or BCL2 overexpression results in asymmetric cell division and aneuploidy. Furthermore, the spindle-assembly checkpoint is functionally linked to apoptosis regulation by BUBR1 (pro-apoptotic) and survivin (anti-apoptotic) proteins. Oncogenic kinases can simultaneously inhibit DNA repair and apoptosis. Moreover, proteins that are involved in DNA repair can participate in the activation of the DNA-damage-induced apoptotic default pathway or, vice versa, apoptosis-regulatory proteins can affect DNA repair. The intricate interplay between apoptosis control and genomic instability is likely to have an important role in oncogenesis. Proteins that determine this interplay include p53, p21 and CHK2, as well as numerous additional effectors that are involved in the DNA-damage and spindle-assembly checkpoints. Such proteins, as well as their immediate afferent and efferent interactors, might constitute therapeutic targets for cancer prevention and treatment.