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Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene

The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. The NHE III(1) region of the c-MYC promoter forms a DNA quadruplex. Stabilization of this structure with small molecules has been shown to reduce expression of c-M...

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Autores principales: Stump, Sascha, Mou, Tung-Chung, Sprang, Stephen R., Natale, Nicholas R., Beall, Howard D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185859/
https://www.ncbi.nlm.nih.gov/pubmed/30312328
http://dx.doi.org/10.1371/journal.pone.0205584
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author Stump, Sascha
Mou, Tung-Chung
Sprang, Stephen R.
Natale, Nicholas R.
Beall, Howard D.
author_facet Stump, Sascha
Mou, Tung-Chung
Sprang, Stephen R.
Natale, Nicholas R.
Beall, Howard D.
author_sort Stump, Sascha
collection PubMed
description The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. The NHE III(1) region of the c-MYC promoter forms a DNA quadruplex. Stabilization of this structure with small molecules has been shown to reduce expression of c-MYC, and targeting the c-MYC quadruplex has become an emerging strategy for development of antitumor compounds. Previous solution NMR studies of the c-MYC quadruplex have assigned the major conformer and topology of this important target, however, regions outside the G-quartet core were not as well-defined. Here, we report a high-resolution crystal structure (2.35 Å) of the major quadruplex formed in the NHE III(1) region of the c-MYC promoter. The crystal structure is in general agreement with the solution NMR structure, however, key differences are observed in the position of nucleotides outside the G-quartet core. The crystal structure provides an alternative model that, along with comparisons to other reported quadruplex crystal structures, will be important to the rational design of selective compounds. This work will aid in development of ligands to target the c-MYC promoter quadruplex with the goal of creating novel anticancer therapies.
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spelling pubmed-61858592018-10-26 Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene Stump, Sascha Mou, Tung-Chung Sprang, Stephen R. Natale, Nicholas R. Beall, Howard D. PLoS One Research Article The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. The NHE III(1) region of the c-MYC promoter forms a DNA quadruplex. Stabilization of this structure with small molecules has been shown to reduce expression of c-MYC, and targeting the c-MYC quadruplex has become an emerging strategy for development of antitumor compounds. Previous solution NMR studies of the c-MYC quadruplex have assigned the major conformer and topology of this important target, however, regions outside the G-quartet core were not as well-defined. Here, we report a high-resolution crystal structure (2.35 Å) of the major quadruplex formed in the NHE III(1) region of the c-MYC promoter. The crystal structure is in general agreement with the solution NMR structure, however, key differences are observed in the position of nucleotides outside the G-quartet core. The crystal structure provides an alternative model that, along with comparisons to other reported quadruplex crystal structures, will be important to the rational design of selective compounds. This work will aid in development of ligands to target the c-MYC promoter quadruplex with the goal of creating novel anticancer therapies. Public Library of Science 2018-10-12 /pmc/articles/PMC6185859/ /pubmed/30312328 http://dx.doi.org/10.1371/journal.pone.0205584 Text en © 2018 Stump et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Stump, Sascha
Mou, Tung-Chung
Sprang, Stephen R.
Natale, Nicholas R.
Beall, Howard D.
Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title_full Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title_fullStr Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title_full_unstemmed Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title_short Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene
title_sort crystal structure of the major quadruplex formed in the promoter region of the human c-myc oncogene
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185859/
https://www.ncbi.nlm.nih.gov/pubmed/30312328
http://dx.doi.org/10.1371/journal.pone.0205584
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