Poly(ADP‐Ribosyl)ation, Genomic Instability, and Longevity

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Abstract
Abstract: Poly(ADP‐ribosyl)ation is a DNA strandbreak‐driven posttranslational modification of nuclear proteins that is catalyzed by poly(ADP‐ribose) polymerase‐1 (PARP‐1), with NAD+ serving as substrate. Recently, additional PARP isoforms were described that seem to account for a minor fraction of cellular poly(ADP‐ribose) synthesis. We have previously described a correlation between poly(ADP‐ribosyl)ation capacity of mononuclear leukocytes of various mammalian species and species‐specific life span. Likewise, lymphoblastoid cell lines derived from human centenarians display a higher poly(ADP‐ribosyl)ation capacity than do controls. At the functional level, recent data show that PARP‐1 is a key regulator of alkylation‐induced sister‐chromatid exchange, imposing a negative control commensurate with the enzyme activity. PARP‐1 activity may therefore be responsible for tuning the rate of genomic instability events that are provoked by the constant attack of endogenous and exogenous genotoxins to a level appropriate for the longevity potential of a given organism or species.