biostudies-literatureWang YHMOH | National Medical Research CouncilNational University of SingaporeAgency for Science, Technology and ResearchMinistry of Education - SingaporeNational Research Foundation SingaporeCancer Prevention and Research Institute of Texase2113233119https://www.ebi.ac.uk/biostudies/studies/S-EPMC8915893biostudies-literatureUnknown119(10)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 Proceedings of the National Academy of Sciences of the United States of AmericaRapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity.PMC8915893CTGIIT18may-0012Mechanobiology Institute core fundingOFIRG17may-061CPRITNRF-CRP22-2019-0003OFIRG19nov-0106A*STAR core fundingNMRC/OFLCG/002-2018NRF-NRFF2015-04Research Centers of Excellence initiativeNRF-CRP23-2019-0004Verkaik NSVenkitaraman ARTam WLWong YLHariharan ASheetz MPvan Gent DCLane DPWang YHHo TLFLee MYGoh HCfalseRapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity.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 2022-01-01T00:00:00Z2022 Mar2025-04-19T20:11:30.981Z2025-04-19T20:11:30.981ZS-EPMC89158933523544810.1073/pnas.2113233119