Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity
YH Wang, Teresa L. Ho, Anushya Hariharan, Hui Chin Goh, Yao Liang Wong, Nicole S. Verkaik, May Yin Lee, Wai Leong Tam, Dik C. van Gent, Ashok R. Venkitaraman, Michael P. Sheetz, David P. Lane
Abstract
SignificanceOur work focuses on the critical longstanding question of the nontranscriptional role of p53 in tumor suppression. We demonstrate here that poly(ADP-ribose) polymerase (PARP)-dependent modification of p53 enables rapid recruitment of p53 to damage sites, where it in turn directs early repair pathway selection. Specifically, p53-mediated recruitment of 53BP1 at early time points promotes nonhomologous end joining over the more error-prone microhomology end-joining. Similarly, p53 directs nucleotide excision repair by mediating DDB1 recruitment. This property of p53 also correlates with tumor suppression in vivo. Our study provides mechanistic insight into how certain transcriptionally deficient p53 mutants may retain tumor-suppressive functions through regulating the DNA damage response.