CRITICAL TELOMERE SHORTENING REGULATED BY THE ATAXIA-TELANGIECTASIA GENE ACTS AS A DNA-DAMAGE SIGNAL LEADING TO ACTIVATION OF P53 PROTEIN AND LIMITED LIFE-SPAN OF HUMAN-DIPLOID FIBROBLASTS - A REVIEW

Somatic tells undergo a limited number of doublings in culture and ent er an irreversible block in the G1 and G2/M phase of the cell cycle te rmed ''senescence''. Telomere shortening presumably as a consequence o f the end-replication problem has been proposed to act as a mitotic cl ock eventually leading to cellular senescence, Several models have bee n proposed to explain how telomere shortening can lead to cellular sen escence, We proposed previously that telomere shortening may eventuall y lead to formation of dicentric chromosomes which on subsequent break age activate a DNA damage response pathway involving the p53 protein, Hence we proposed that the telomere shortening signal is perceived by the cell as DNA damage. Recently we have obtained experimental evidenc e that the p53 protein is activated posttranslationally in human fibro blasts which undergo telomere shortening and subsequent senescence in culture, In this paper we also show that the increased activity of p53 protein coincides with formation of dicentric chromosomes and senesce nce. Also, we have previously found that an increase in the level of t he down stream target of p53 protein, p21(WAF1/SDI1/CIP1), is dependen t on both p53 and p300 proteins. We have also shown that fibroblasts o btained from individuals with Ataxia Telangiectasia lose telomeric DNA al an accelerated rate, activate p53 protein, and undergo premature s enescence in culture, These results suggest that the ataxia-telangiect asia gene (ATM) and p53 are involved in surveillance and regulation of telomeric DNA. Once a critical length of telomeric DNA is reached, AT M and p53 sense and relay this signal to the cell cycle leading to sen escence.