Genetics of cellular senescence.

Cellular senescence or replicative senescence is a state of irreversible growth arrest that somatic cells enter as a result of replicative exhaustion. This can be mimicked by culture manipulations such as Ras oncogene overexpression or treatment with various agents such as sodium butyrate and 5-azacytidine. It is believed that cellular senescence is one of the protective mechanisms against tumor formation. Genetic analyses of cellular senescence have revealed that it is dominant over immortality because whole cell fusion of normal with immortal cells yields hybrids with limited division potential. Only four complementation groups for indefinite division have been identified from extensive studies fusing different immortal human cell lines with each other. The senescence-related genes for three of the complementation groups B-D have been identified on human chromosomes 4, 1, and 7, respectively, by microcell-mediated chromosome transfer, though the existence of senescence-related genes on other chromosomes has been suggested. MORF4 was cloned as the senescence-related gene on human chromosome 4 and is a member of a new gene family, which has multiple transcription factor-like motifs. This gene family may affect cell division by modulating gene expression. Study of this novel gene family should lead to new insights regarding the mechanisms and function of cellular senescence in aging and immortalization.