Dokument

Summary:
CHD4/Mi-2 is a highly conserved ATP-dependent chromatin remodeller. It is essential in processes like transcription regulation, DNA damage response, cell cycle progression, as well as differentiation and development in eukaryotes. It is one of the catalytic components of the NuRD (nucleosome remodelling and deacetlyation) complex. ATP-dependent chromatin remodellers, including CHD4, are frequently mutated in human cancers. In this study, the effects of several missense mutations derived from endometrial cancer patients were analysed using dMi-2, a Drosophila melanogaster homologue of human CHD4, as a model. Selected point mutants, covering key domains and regions in dMi-2, were biochemically analysed. It was demonstrated through enzymatic and non-enzymatic assays that these mutations can have a wide variety of effects on nucleosome binding, ATP hydrolysis and nucleosome remodelling. Interestingly, this analysis uncovered that these mutations can impact dMi-2 in opposite manners, by lowering or increasing the protein’s remodelling ability. Some mutations caused changes in the coupling of ATP hydrolysis with nucleosome remodelling, revealing new roles of certain residues and regions in modulating protein activity. Additionally, a new regulatory region was identified in the C-terminal part of the protein, which is comparable to previously identified regulatory regions in CHD1, ISWI and Snf2. On the N-terminal side, analysis of chromodomain mutants allowed identification of a structural element in dMi-2, similar to one identified in CHD1, that likely contacts nucleosomal DNA during remodelling. Furthermore, in vivo genetic experiments in Drosophila melanogaster demonstrated that expression of selected dMi-2 point mutants can cause misregulation in development of epithelial wing structures. These phenotypes correlated with the nucleosome remodelling characteristics of dMi-2 point mutants. Together, the findings of this thesis give new insight into the consequences of mutations of chromatin remodellers in cancer and provide a basis for understanding molecular mechanisms used by the Mi-2 mutants to contribute to carcinogenesis.

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