P53, P63, and P73 proteins belong to the P53 family of transcription factors, sharing a common gene organization that, from the P1 and P2 promoters, produces two groups of mRNAs encoding proteins with different N-terminal regions; moreover, alternative splicing events at C-terminus further contribute to the generation of multiple isoforms. P53 family proteins can influence a plethora of cellular pathways mainly through the direct binding to specific DNA sequences known as response elements (REs), and the transactivation of the corresponding target genes. However, the transcriptional activation by P53 family members can be regulated at multiple levels, including the DNA topology at responsive promoters. Here, by using a yeast-based functional assay, we evaluated the influence that a G-quadruplex (G4) prone sequence adjacent to the p53 RE derived from the apoptotic PUMA target gene can exert on the transactivation potential of full-length and N-terminal truncated P53 family α isoforms (wild-type and mutant). Our results show that the presence of a G4 prone sequence upstream or downstream of the P53 RE leads to significant changes in the relative activity of P53 family proteins, emphasizing the potential role of structural DNA features as modifiers of P53 family functions at target promoter sites.

Department of Experimental Biology Faculty of Science Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Food Chemistry and Biotechnology Faculty of Chemistry Brno University of Technology Purkyňova 118 61200 Brno Czech Republic

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Largo P Daneo 3 16132 Genoa Italy

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 61265 Brno Czech Republic

Laboratory of Transcriptional Networks Department of Cellular Computational and Integrative Biology CIBIO University of Trento via Sommarive 9 38123 Trento Italy

Medical Genetics Unit IRCCS Istituto Giannina Gaslini via G Gaslini 5 16147 Genoa Italy

Mutagenesis and Cancer Prevention Unit IRCCS Ospedale Policlinico San Martino 16132 Genoa Italy

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