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

Kristina Kovač, Anja Sauer, Igor Mačinković, Stephan Awe, Florian Finkernagel, Helen Hoffmeister, Andreas Fuchs, Rolf Müller, Christina Rathke, Gernot Längst and Alexander Brehm ()
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Kristina Kovač: University of Marburg
Anja Sauer: University of Marburg
Igor Mačinković: University of Marburg
Stephan Awe: University of Marburg
Florian Finkernagel: University of Marburg
Helen Hoffmeister: University of Regensburg
Andreas Fuchs: University of Regensburg
Rolf Müller: University of Marburg
Christina Rathke: Philipps-University Marburg
Gernot Längst: University of Regensburg
Alexander Brehm: University of Marburg

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04503-2

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