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

Kristina Kovač1, Anja Sauer1, Igor Mačinković1

  • 1Institute for Molecular Biology and Tumour Research, University of Marburg, 35043, Marburg, Germany.

Nature Communications
|May 31, 2018
PubMed

Insights

Mutations in ATP-dependent chromatin remodellers, found in over 20% of cancers, have diverse effects on enzyme function. This study reveals how specific CHD4 mutations impact cancer by altering DNA remodelling properties.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • ATP-dependent chromatin remodellers are frequently mutated in human cancers.
  • The functional consequences of these mutations on enzyme activity are not well understood.

Purpose of the Study:

  • To characterize the effects of CHD4 mutations found in endometrial carcinoma on the remodelling properties of its Drosophila homologue, dMi-2.
  • To elucidate the mechanistic defects of CHD4 in cancer and inform potential therapeutic strategies.

Main Methods:

  • Biochemical assays to assess nucleosome binding, ATPase activity, and nucleosome remodelling of dMi-2 mutants.
  • Genetic experiments in Drosophila to evaluate the in vivo consequences of cancer-derived dMi-2 mutations.

Main Results:

  • CHD4 mutations exhibit diverse defects in nucleosome binding, ATPase activity, and remodelling, with some increasing enzyme activity.
  • The chromodomains and a novel regulatory region are identified as crucial for nucleosome remodelling.
  • Expression of cancer-derived dMi-2 mutants in Drosophila leads to misregulation of epithelial wing structure differentiation, correlating with remodelling properties.

Conclusions:

  • Cancer-associated CHD4 mutations have varied impacts on enzyme function, affecting chromatin remodelling.
  • Understanding these mechanistic defects provides a foundation for developing therapies to restore CHD4 activity in cancer.

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