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EEC- and ADULT-Associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences

Authors

  • Paola Monti,

    1. Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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  • Debora Russo,

    1. Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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  • Renata Bocciardi,

    1. Laboratory of Molecular Genetics, G. Gaslini Institute, Genoa, Italy
    2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
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  • Giorgia Foggetti,

    1. Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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  • Paola Menichini,

    1. Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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  • Maria T. Divizia,

    1. Laboratory of Molecular Genetics, G. Gaslini Institute, Genoa, Italy
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  • Margherita Lerone,

    1. Laboratory of Molecular Genetics, G. Gaslini Institute, Genoa, Italy
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  • Claudio Graziano,

    1. Unità di Genetica Medica, Azienda Ospedaliera Universitaria Policlinico S. Orsola Malpighi, Bologna, Italy
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  • Anita Wischmeijer,

    1. Unità di Genetica Medica, Azienda Ospedaliera Universitaria Policlinico S. Orsola Malpighi, Bologna, Italy
    2. Clinical Genetics Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
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  • Hector Viadiu,

    1. Laboratory of Structural Biochemistry, Department of Chemistry and Biochemistry, University of California, San Diego, California
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  • Roberto Ravazzolo,

    1. Laboratory of Molecular Genetics, G. Gaslini Institute, Genoa, Italy
    2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
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  • Alberto Inga,

    Corresponding author
    • Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy
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  • Gilberto Fronza

    Corresponding author
    • Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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  • Additional Supporting Information may be found in the online version of this article.

  • Contract grant sponsors: Italian Association for Cancer Research (Associazione Italiana per la Ricerca sul Cancro) (IG#9086, IG#5506); the Hellman Foundation, University of California Senate; American Cancer Society/Internal Research; and the Italian Ministry of Health (RFPS-2007-4-631972).

  • Communicated by Sergio Ottolenghi

Correspondence to: Alberto Inga, Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento 38060, Italy. E-mail: inga@science.unitn.it or Gilberto Fronza, Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa 16132, Italy. E-mail: gilberto.fronza@istge.it

ABSTRACT

TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild-type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN-P63α-specific REs derived from genes closely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.

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