title: Gain-of-function p53 mutants have widespread genomic locations partially overlapping with p63.
abstract: p53 and p63 are transcription factors -TFs- playing master roles in the DNA-damage response and in the development and maintenance of pluristratified epithelia, respectively. p53 mutations are common in epithelial tumors and HaCaT keratinocytes harbor two p53 alleles -H179Y and R282Q- with gain-of-function (GOF) activity. Indeed, functional inactivation of mutp53 affects the growth rate of HaCaT. We investigated the strategy of mutp53, by performing ChIP-Seq experiments of mutp53 and p63 and analyzed the transcriptome after mutp53 inactivation. Mutp53 bind to 7135 locations in vivo, with a robust overlap with p63. De novo motifs discovery recovered a p53/p63RE with high information content in sites bound by p63 and mutp53/p63, but not by mutp53 alone: these sites are rather enriched in elements of other TFs. The HaCaT p63 locations are only partially overlapping with those of normal keratinocytes; importantly, and enriched in mutp53 sites which delineate a functionally different group of target genes. Our data favour a model whereby mutp53 GOF mutants act both by tethering growth-controlling TFs and highjacking p63 to new locations.
authors.affiliation: Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Martynova
authors.forename: Silvia
authors.initials: S
authors.lastname: Pozzi
authors.forename: Valentina
authors.initials: V
authors.lastname: Basile
authors.forename: Diletta
authors.initials: D
authors.lastname: Dolfini
authors.forename: Federico
authors.initials: F
authors.lastname: Zambelli
authors.forename: Carol
authors.initials: C
authors.lastname: Imbriano
authors.forename: Giulio
authors.initials: G
authors.lastname: Pavesi
authors.forename: Roberto
authors.initials: R
authors.lastname: Mantovani
mesh_terms: D017209:Apoptosis / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA