DNA excision repair and DNA damage-induced apoptosis are linked to poly(ADP-ribosyl)ation but have different requirements for p53

Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein tha t catalyzes the transfer of;ADP-ribose residues from NAD(+) to itself and d ifferent chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair a nd DNA damage-induced cell death. We have generated transgenic mice that la ck PARP activity in thymocytes owing to the targeted expression of a domina nt negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apopt osis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity a fter DNA damage and correlates with an accelerated onset of Fax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regar dless of p53 status. We found the same increased susceptibility to apoptosi s in PARP null mice, a similar inhibition of DNA repair kinetics, and the s ame upregulation of p53 in response to DNA damage. Thus, based on two diffe rent experimental in vivo models, we identify a direct, p53-independent, fu nctional connection between poly(ADP-ribosyl)ation and the DNA excision rep air machinery. Furthermore, we propose a p53-dependent link between PARP ac tivity and DNA damage-induced cell death.