Poly(ADP-ribosyl)ation: a posttranslational protein modification linked with genome protection and mammalian longevity

Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear prote ins catalysed by the 113-kDa enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and, to a lesser extent, by several other recently described polypeptides. The catalytic function of PARP-1 is directly stimulated by DNA strand break s, thus making poly(ADP-ribosyl)ation one of the immediate cellular respons es to oxidative and other types of DNA damage. Poly(ADP-ribosyl)ation plays an important role in the recovery of proliferating cells from certain type s of DNA damage, and this has been linked mechanistically with an involveme nt in DNA base-excision repair. Furthermore PARP-1 activity is necessary to maintain genomic stability under conditions of genotoxic stress and is act ually a key regulator of alkylation-induced sister-chromatid exchange forma tion, imposing a control that is strictly negative and commensurate with th e enzyme activity level. Finally, there is a positive correlation between t he poly(ADP-ribosyl)ation capacity of mononuclear leukocytes of various mam malian species and species-specific life span. Likewise, lymphoblastoid cel l lines derived From human centenarians display a higher poly(ADP-ribosyl)a tion capacity than controls. In conclusion, PARP-1 may be viewed as a facto r that is responsible for downregulating the rate of genomic instability ev ents, which are provoked by the constant attack by endogenous and exogenous DNA-damaging agents, in such a way as to tune them to a level which is jus t appropriate for the life span potential of a given species.