Abstract

Poly(ADP‐ribose) polymerase‐1 (PARP‐1) safeguards genomic integrity by limiting sister chromatid exchanges. Overstimulation of PARP‐1 by extensive DNA damage, however, can result in cell death, as prolonged PARP‐1 activation depletes NAD+, a substrate, and elevates nicotinamide, a product. The decline of NAD+ and the rise of nicotinamide may downregulate the activity of Sir2, the NAD+‐dependent deacetylases, because deacetylation by Sir2 is dependent on high concentration of NAD+ and inhibited by physiologic level of nicotinamide. The Sir2 deacetylase family has been implicated in mediating gene silencing, longevity and genome stability. It is conceivable that poly(ADP‐ribosyl)ation by PARP‐1, which is induced by DNA damage, could modulate protein deacetylation by Sir2 via the NAD+/nicotinamide connection. The possible linkage of the two ancient pathways that mediate broad biological activities may spell profound evolutionary roles for the conserved PARP‐1 and Sir2 gene families in multicellular eukaryotes. BioEssays 25:808–814, 2003. © 2003 Wiley Periodicals, Inc.