Telomeres, Checkpoints and Chromosomal Instability

摘要

Genetic instability as it occurs in cancer appears to occur by a variety of mechanisms. Notable examples include microsatellite instability associated with genetic defects in heteroduplex and mismatch repair (e.g. MLH1), chromosome number instability associated with genetic defects in spindle-damage checkpoint function (e.g. BUB1), and chromosome structure instability associated with genetic defects in DNA repair (BRCA1) and DNA damage checkpoint function (ATM). A common theme uniting all forms of genetic instability is the presence of mutations in genes that are needed for the complete and accurate replication and segregation of the genome during the cell division cycle. Thus cancer can be thought of as a disease of aberrant DNA metabolism. Its malignant characteristic of progression to higher stage and grade may be a direct consequence of the elevated mutation rate that derives from the primary defect in DNA metabolism. The tumour suppressor gene TP53 is not commonly thought of as an element of DNA metabolism. However, recent data link its function to nucleotide excision repair through transactivation of p48/XPE, which stimulates global excision repair of UV-radiation-induced pyrimidine dimers. TP53-dependent transactivation of the cyclin-dependent kinase inhibitor CDKN1A also should contribute to DNA repair by delaying the initiation of DNA replication and thereby providing more time for repair. The DNA damage G_1-phase checkpoint function served by TP53 through CDKN1A also stabilises chromosomes by arresting growth at the time of senescence. This replicative senescence checkpoint suppresses the growth of cells with critically eroded, unstable telomeres. Our studies of telomeres, checkpoints and chromosomal instability point to a complex gestalt of interacting systems that deteriorate when TP53 function is ablated. The TP53 sobriquet, guardian of the genome, is well-deserved.