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September 5th, 2025
Version: 2
University of Lodz
molecular biology
bioRxiv

P53 supresses transcription of the p300-E2F1-dependent gene subset by maintaining KDM5B associated with gene promoters

Gronkowska, K.Open in Google Scholar•Kolacz-Milewska, K.Open in Google Scholar•Michlewska, S.Open in Google Scholar•Robaszkiewicz, A.Open in Google Scholar

p53 is a transcription activator or repressor that acts mainly by having direct control over the expression of CDK inhibitor - p21 in response to DNA damage. In this study, molecular evidence was provided for the occurrence of p53 at the subset of E2F1-driven promoters and their suppression, despite the co-occurrence of p53 with p300. P53 repressed promoters were characterized by relatively high nucleosome density and demethylation of H3K4, followed by low H3K27 acetylation and trimethylation of H3K4. Induction of the ATM/ATR-Chek1/2-p53 pathway by sub-lethal doses of cisplatin caused the release of p53 from gene promoters, chromatin relaxation and the gain of transcription permissive histone marks. Mechanistically, p53 maintained the KDM5B that is associated with gene promoters, thereby conditioning the demethylation of H3K4me3. P53 formed an immunoprecipitable complex with KDM5B, E2F1, p300 and H3K4me2 in intact cells, which decomposed with cisplatin and substantially increased the level of H3K4me3 in the p300 interactome. The extrusion of KDM5B from the chromatin was triggered by cisplatin, transient p53 silencing or KDM5B inhibition, also enabled p300 enrichment and increased gene transcription. In summary, p53 directly suppressed the subset of E2F1-driven genes in proliferating cells by maintaining KDM5B associated with gene promoters and inhibiting p300-mediated transcription.

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