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p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia

Expansions of trinucleotide repeats (TNRs) are associated with genetic disorders such as Friedreich’s ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. Sequence and structure-selective modes of DNA recognition are among the main attribute...

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Autores principales: Helma, Robert, Bažantová, Pavla, Petr, Marek, Adámik, Matej, Renčiuk, Daniel, Tichý, Vlastimil, Pastuchová, Alena, Soldánová, Zuzana, Pečinka, Petr, Bowater, Richard P., Fojta, Miroslav, Brázdová, Marie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600395/
https://www.ncbi.nlm.nih.gov/pubmed/31159174
http://dx.doi.org/10.3390/molecules24112078
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author Helma, Robert
Bažantová, Pavla
Petr, Marek
Adámik, Matej
Renčiuk, Daniel
Tichý, Vlastimil
Pastuchová, Alena
Soldánová, Zuzana
Pečinka, Petr
Bowater, Richard P.
Fojta, Miroslav
Brázdová, Marie
author_facet Helma, Robert
Bažantová, Pavla
Petr, Marek
Adámik, Matej
Renčiuk, Daniel
Tichý, Vlastimil
Pastuchová, Alena
Soldánová, Zuzana
Pečinka, Petr
Bowater, Richard P.
Fojta, Miroslav
Brázdová, Marie
author_sort Helma, Robert
collection PubMed
description Expansions of trinucleotide repeats (TNRs) are associated with genetic disorders such as Friedreich’s ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. Sequence and structure-selective modes of DNA recognition are among the main attributes of p53 protein. The focus of this work was analysis of the p53 structure-selective recognition of TNRs associated with human neurodegenerative diseases. Here, we studied binding of full length p53 and several deletion variants to TNRs folded into DNA hairpins or loops. We demonstrate that p53 binds to all studied non-B DNA structures, with a preference for non-B DNA structures formed by pyrimidine (Py) rich strands. Using deletion mutants, we determined the C-terminal DNA binding domain of p53 to be crucial for recognition of such non-B DNA structures. We also observed that p53 in vitro prefers binding to the Py-rich strand over the purine (Pu) rich strand in non-B DNA substrates formed by sequence derived from the first intron of the frataxin gene. The binding of p53 to this region was confirmed using chromatin immunoprecipitation in human Friedreich’s ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to TNRs’ non-B DNA structures.
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spelling pubmed-66003952019-07-16 p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia Helma, Robert Bažantová, Pavla Petr, Marek Adámik, Matej Renčiuk, Daniel Tichý, Vlastimil Pastuchová, Alena Soldánová, Zuzana Pečinka, Petr Bowater, Richard P. Fojta, Miroslav Brázdová, Marie Molecules Article Expansions of trinucleotide repeats (TNRs) are associated with genetic disorders such as Friedreich’s ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. Sequence and structure-selective modes of DNA recognition are among the main attributes of p53 protein. The focus of this work was analysis of the p53 structure-selective recognition of TNRs associated with human neurodegenerative diseases. Here, we studied binding of full length p53 and several deletion variants to TNRs folded into DNA hairpins or loops. We demonstrate that p53 binds to all studied non-B DNA structures, with a preference for non-B DNA structures formed by pyrimidine (Py) rich strands. Using deletion mutants, we determined the C-terminal DNA binding domain of p53 to be crucial for recognition of such non-B DNA structures. We also observed that p53 in vitro prefers binding to the Py-rich strand over the purine (Pu) rich strand in non-B DNA substrates formed by sequence derived from the first intron of the frataxin gene. The binding of p53 to this region was confirmed using chromatin immunoprecipitation in human Friedreich’s ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to TNRs’ non-B DNA structures. MDPI 2019-05-31 /pmc/articles/PMC6600395/ /pubmed/31159174 http://dx.doi.org/10.3390/molecules24112078 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Helma, Robert
Bažantová, Pavla
Petr, Marek
Adámik, Matej
Renčiuk, Daniel
Tichý, Vlastimil
Pastuchová, Alena
Soldánová, Zuzana
Pečinka, Petr
Bowater, Richard P.
Fojta, Miroslav
Brázdová, Marie
p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title_full p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title_fullStr p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title_full_unstemmed p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title_short p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
title_sort p53 binds preferentially to non-b dna structures formed by the pyrimidine-rich strands of gaa·ttc trinucleotide repeats associated with friedreich’s ataxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600395/
https://www.ncbi.nlm.nih.gov/pubmed/31159174
http://dx.doi.org/10.3390/molecules24112078
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