Tumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner

Nature Communications
Kristina KovačA Brehm

Abstract

ATP-dependent chromatin remodellers are mutated in more than 20% of human cancers. The consequences of these mutations on enzyme function are poorly understood. Here, we characterise the effects of CHD4 mutations identified in endometrial carcinoma on the remodelling properties of dMi-2, the highly conserved Drosophila homologue of CHD4. Mutations from different patients have surprisingly diverse defects on nucleosome binding, ATPase activity and nucleosome remodelling. Unexpectedly, we identify both mutations that decrease and increase the enzyme activity. Our results define the chromodomains and a novel regulatory region as essential for nucleosome remodelling. Genetic experiments in Drosophila demonstrate that expression of cancer-derived dMi-2 mutants misregulates differentiation of epithelial wing structures and produces phenotypes that correlate with their nucleosome remodelling properties. Our results help to define the defects of CHD4 in cancer at the mechanistic level and provide the basis for the development of molecular approaches aimed at restoring their activity.

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Citations

Jan 17, 2019·The Journal of Biological Chemistry·Helen HoffmeisterGernot Längst
Nov 9, 2019·Nucleic Acids Research·Igor MačinkovićAlexander Brehm
Nov 13, 2019·Nucleic Acids Research·Engin DemirdizenSylvia Erhardt
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May 14, 2021·Frontiers in Oncology·Apolonia NovilloPablo Gómez-Del Arco
Jun 3, 2021·International Journal of Molecular Sciences·Cedric R Clapier
Dec 21, 2021·Immunological Reviews·James R HagmanBrian P O'Connor

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Methods Mentioned

BETA
RNAseq
filter binding
electrophoretic mobility shift assay
electrophoresis
transgenic
histone acetylation
PCR

Software Mentioned

Science Lab Image Gauge ( FUJIFILMS )
Science Lab Image Gauge ( FUJIFILM )

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