유전적 불안정성 과 세포 사멸사

Genomic Instability and Apoptosis

Genome integrity and cell proliferation and survival are regulated by an intricate network of pathways that include cell-cycle checkpoints, DNA repair and recombination, and program m ed cell death. Permanent or transient genomic instability, which represents one of the fundamental characteristics of cancer, might be ascribed to deficiencies in numerous cellular processes including mitotic-checkpoint regulation, and DNA damage signalling and repair, as well as telomere maintenance and centrosome function. This review will focus on the complex interplay between genomic instability and apoptosis regulation that participates in carcinogenesis. The relationship between genomic integrity and cell-death regulation can follow at least three different non-exclusive patterns, all of which might be important for the development of cancer. First, genomic instability can lead to the mutation, or altered expression levels, of cell-death regulators. Second, disabled apoptosis can favor genomic instability. Indeed, numerous cellular mechanisms enforce the rule ’better dead than wrong , which means that cells that have a damaged genome or are afflicted by many disorders will be aborted by apoptosis - thereby avoiding the propagation of potentially oncogenic mutations. DNA double-strand breaks (DSBs), telomere dysflinction, illicit polyploidy or abnormal mitoses can directly trigger apoptosis through a default pathway. However, if apoptosis is inhibited for some reason, this increases the risk of chromosomal instability (CIN) at several levels, and cells that are sufficiently fit to survive can be at a growth advantage, which can lead to cancer. Third, a single protein or process might be involved in the control of both apoptosis and genomic instability, which allows crosstalk between the processes. Here, we will discuss these different possibilities, their molecular mechanisms and their possible impact on carcinogenesis.