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Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations

Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure...

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Detalles Bibliográficos
Autores principales: Farnung, Lucas, Ochmann, Moritz, Cramer, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338049/
https://www.ncbi.nlm.nih.gov/pubmed/32543371
http://dx.doi.org/10.7554/eLife.56178
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author Farnung, Lucas
Ochmann, Moritz
Cramer, Patrick
author_facet Farnung, Lucas
Ochmann, Moritz
Cramer, Patrick
author_sort Farnung, Lucas
collection PubMed
description Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure of Homo sapiens CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the ‘twist defect’ model of chromatin remodeling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our structure also maps CHD4 mutations that are associated with human cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome.
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spelling pubmed-73380492020-07-13 Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations Farnung, Lucas Ochmann, Moritz Cramer, Patrick eLife Biochemistry and Chemical Biology Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure of Homo sapiens CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the ‘twist defect’ model of chromatin remodeling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our structure also maps CHD4 mutations that are associated with human cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome. eLife Sciences Publications, Ltd 2020-06-16 /pmc/articles/PMC7338049/ /pubmed/32543371 http://dx.doi.org/10.7554/eLife.56178 Text en © 2020, Farnung et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Farnung, Lucas
Ochmann, Moritz
Cramer, Patrick
Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title_full Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title_fullStr Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title_full_unstemmed Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title_short Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations
title_sort nucleosome-chd4 chromatin remodeler structure maps human disease mutations
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338049/
https://www.ncbi.nlm.nih.gov/pubmed/32543371
http://dx.doi.org/10.7554/eLife.56178
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