Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation

Poly( ADP- ribose) polymerase 1 (PARP- 1) and p53 are two key proteins in the DNA-damage response. Although PARP1 is known to poly( ADP- ribosyl) ate p53, the role of this modification remains elusive. Here, we identify the major poly( ADP- ribosyl) ated sites of p53 by PARP- 1 and find that PARP-1-mediated poly( ADP- ribosyl) ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP- 1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage. PARP- 1 becomes super-activated by binding to damaged DNA, which in turn poly( ADP- ribosyl) ates p53. The nuclear export machinery is unable to target poly( ADP- ribosyl) ated p53, promoting accumulation of p53 in the nucleus where p53 exerts its transactivational function.