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|Title:||Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity||Authors:||Wang, Yu-Hsiu
Ho, Teresa L. F.
Goh, Hui Chin
Wong, Yao Liang
Verkaik, Nicole S.
Lee, May Yin
Tam, Wai Leong
van Gent, Dik C.
Venkitaraman, Ashok R.
Sheetz, Michael P.
Lane, David P.
|Keywords:||Science::Biological sciences||Issue Date:||2022||Source:||Wang, Y., Ho, T. L. F., Hariharan, A., Goh, H. C., Wong, Y. L., Verkaik, N. S., Lee, M. Y., Tam, W. L., van Gent, D. C., Venkitaraman, A. R., Sheetz, M. P. & Lane, D. P. (2022). Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity. Proceedings of the National Academy of Sciences of the United States of America, 119(10), e2113233119-. https://dx.doi.org/10.1073/pnas.2113233119||Project:||OFIRG17may-061
|Journal:||Proceedings of the National Academy of Sciences of the United States of America||Abstract:||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 end-joining (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.||URI:||https://hdl.handle.net/10356/162569||ISSN:||0027-8424||DOI:||10.1073/pnas.2113233119||Schools:||School of Biological Sciences||Organisations:||Cancer Science Institute of Singapore, NUS
Genome Institute of Singapore, A*STAR
Yong Loo Lin School of Medicine, NUS
|Rights:||© The Authors. This open access article is distributed under Creative Commons AttributionNonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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