Poly(ADP-ribose) polymerase-1 is a positive regulator of the p53-mediated cell cycle response to ionizing radiation

Poly(ADP-ribose) polymerase-1 (PARP-1) and p53 are both activated by genotoxic stress. To investigate the role of PARP-1 in the p53 response to ionizing radiation (IR), PARP-1 poly(ADP-ribosyl)ation function was disrupted in MCF-7 and BJ/TERT cells by chemical inhibition with 1,5-dihydroxyisoquinoline (IQ), and trans-dominant inhibition by overexpression of the PARP-1 DNA binding domain (DBD). Analysis of PARP activity showed that PARP-1 is the only species detected capable of self-poly(ADP-ribosyl)ation in BJ/TERT and MCF-7 cells. IQ treatment prior to IR led to a delay and attenuation of the induction of two p53-responsive genes, p21 and mdm-2, and abrogation of p53-mediated G1 arrest in both BJ/TERT and MCF-7 cells. Transient overexpression of the PARP-1 DBD in MCF-7 cells led to a similar delay and attenuation in p21 induction and suppression of the p53-mediated G1 arrest following IR. This study shows that PARP-1 is a critical regulator of the p53 response to DNA damage.