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Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based cl...

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Autores principales: Osterburg, Christian, Ferniani, Marco, Antonini, Dario, Frombach, Ann-Sophie, D’Auria, Ludovica, Osterburg, Susanne, Lotz, Rebecca, Löhr, Frank, Kehrloesser, Sebastian, Zhou, Huiqing, Missero, Caterina, Dötsch, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113246/
https://www.ncbi.nlm.nih.gov/pubmed/37072394
http://dx.doi.org/10.1038/s41419-023-05796-y
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author Osterburg, Christian
Ferniani, Marco
Antonini, Dario
Frombach, Ann-Sophie
D’Auria, Ludovica
Osterburg, Susanne
Lotz, Rebecca
Löhr, Frank
Kehrloesser, Sebastian
Zhou, Huiqing
Missero, Caterina
Dötsch, Volker
author_facet Osterburg, Christian
Ferniani, Marco
Antonini, Dario
Frombach, Ann-Sophie
D’Auria, Ludovica
Osterburg, Susanne
Lotz, Rebecca
Löhr, Frank
Kehrloesser, Sebastian
Zhou, Huiqing
Missero, Caterina
Dötsch, Volker
author_sort Osterburg, Christian
collection PubMed
description The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based classification. In this study we provide a detailed investigation of all currently known mutations in the p63 DBD, which are associated with developmental syndromes, by measuring their impact on transcriptional activity, DNA binding affinity, zinc binding capacity and thermodynamic stability. Some of the mutations we have further characterized with respect to their ability to convert human dermal fibroblasts into induced keratinocytes. Here we propose a classification of the p63 DBD mutations based on the four different mechanisms of DNA binding impairment which we identified: direct DNA contact, zinc finger region, H2 region, and dimer interface mutations. The data also demonstrate that, in contrast to p53 cancer mutations, no p63 mutation induces global unfolding and subsequent aggregation of the domain. The dimer interface mutations that affect the DNA binding affinity by disturbing the interaction between the individual DBDs retain partial DNA binding capacity which correlates with a milder patient phenotype.
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spelling pubmed-101132462023-04-20 Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree Osterburg, Christian Ferniani, Marco Antonini, Dario Frombach, Ann-Sophie D’Auria, Ludovica Osterburg, Susanne Lotz, Rebecca Löhr, Frank Kehrloesser, Sebastian Zhou, Huiqing Missero, Caterina Dötsch, Volker Cell Death Dis Article The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based classification. In this study we provide a detailed investigation of all currently known mutations in the p63 DBD, which are associated with developmental syndromes, by measuring their impact on transcriptional activity, DNA binding affinity, zinc binding capacity and thermodynamic stability. Some of the mutations we have further characterized with respect to their ability to convert human dermal fibroblasts into induced keratinocytes. Here we propose a classification of the p63 DBD mutations based on the four different mechanisms of DNA binding impairment which we identified: direct DNA contact, zinc finger region, H2 region, and dimer interface mutations. The data also demonstrate that, in contrast to p53 cancer mutations, no p63 mutation induces global unfolding and subsequent aggregation of the domain. The dimer interface mutations that affect the DNA binding affinity by disturbing the interaction between the individual DBDs retain partial DNA binding capacity which correlates with a milder patient phenotype. Nature Publishing Group UK 2023-04-18 /pmc/articles/PMC10113246/ /pubmed/37072394 http://dx.doi.org/10.1038/s41419-023-05796-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Osterburg, Christian
Ferniani, Marco
Antonini, Dario
Frombach, Ann-Sophie
D’Auria, Ludovica
Osterburg, Susanne
Lotz, Rebecca
Löhr, Frank
Kehrloesser, Sebastian
Zhou, Huiqing
Missero, Caterina
Dötsch, Volker
Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title_full Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title_fullStr Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title_full_unstemmed Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title_short Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree
title_sort disease-related p63 dbd mutations impair dna binding by distinct mechanisms and varying degree
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113246/
https://www.ncbi.nlm.nih.gov/pubmed/37072394
http://dx.doi.org/10.1038/s41419-023-05796-y
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