Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity

Yu Hsiu Wang, Teresa L.F. 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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


p53 is primarily known as a downstream transcriptional effector in the DNA damage-response cascade. We report that endogenous p53 rapidly accumulates at DNA damage sites within 2 s of UVA microirradiation. The kinetics of p53 recruitment mimics those of known DNA damage-response proteins, such as Ku70 and poly(- ADP-ribose) polymerase (PARP), and precedes recruitment of Nbs1, 53BP1, and DDB1. Mutations in the DNA-binding and C-terminal domains significantly suppress this rapid recruitment. The C-terminal domain of p53 contains key residues for PARP interaction that are required for rapid recruitment of p53 to DNA damage sites, as is PARP-dependent modification. The presence of p53 at damage sites influences the recruitment kinetics of 53BP1 and DDB1 and directs the choice of nonhomologous end joining repair (NHEJ) and nucleotide excision repair. Mutations that suppressed rapid recruitment of p53 promoted error-prone alternative endjoining (alt-NHEJ) and inhibited nucleotide excision repair. Our finding that p53 is a critical early responder to DNA damage stands in contrast with its extensively studied role as a downstream transcriptional regulator in DNA damage repair. We highlight an unrecognized role of p53 in directing DNA repair dynamics and integrity and suggest a parallel mode of p53 tumor suppression apart from its function as a transcription factor.

Original languageEnglish (US)
Article numbere2113233119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Mar 8 2022
Externally publishedYes


  • DNA repair
  • Laser microirradiation
  • Recruitment kinetics
  • Tumor suppression
  • p53

ASJC Scopus subject areas

  • General


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