Are poly(ADP-ribosyl)ation by PARP-1 and deacetylation by Sir2 linked?
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.
Zhang
Jie
J
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224. zhangj@guilfordpharm.com
D000818:Animals; D004734:Energy Metabolism; D006801:Humans; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000096:biosynthesis; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D009243:NAD; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D037761:Sirtuins