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

Kovač, Kristina; Sauer, A.; Macinkovic, Igor; Awe, Stephan; Finkernagel, Florian; Hoffmeister, Helen; Fuchs, Andreas; Müller, Rolf; Rathke, Christina; Längst, Gernot; Brehm, Alexander

doi:10.1038/s41467-018-04503-2

Cited by 36 publications

(40 citation statements)

References 63 publications

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“…Even in the absence of other NuRD subunits, CHD4 can reposition an asymmetric mononucleosome substrate bearing different lengths of DNA at the two sides of the histone octamer, yielding a more symmetric structure (Levendosky et al, 2016, Kovac et al, 2018. However, this activity is much weaker in comparison to CHD1 (Watson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

CHD4 slides nucleosomes by decoupling entry- and exit-side DNA translocation

Zhong

Paudel

Ryan³

et al. 2019

Preprint

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Chromatin remodellers hydrolyse ATP to move nucleosomal DNA against histone octamers. The mechanism, however, is only partially resolved, and unclear if it is conserved among the four remodeller families. Here we use single-molecule assays to examine the mechanism of action of CHD4, which is part of the least well understood family of remodellers. We demonstrate that the binding energy for CHD4-nucleosome complex formation -even in the absence of nucleotidetriggers significant conformational changes in DNA at the entry side, effectively priming the system for remodelling. During remodelling, flanking DNA enters the nucleosome in a continuous, gradual manner but exits in concerted 4-6 base-pair steps. This decoupling of entry-and exit-side translocation suggests that ATP-driven movement of entry-side DNA builds up strain inside the nucleosome that is subsequently released at the exit side by DNA expulsion. We propose a mechanism for nucleosome sliding based on these and published data.

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Section: Introductionmentioning

confidence: 99%

CHD4 slides nucleosomes by decoupling entry- and exit-side DNA translocation

Zhong

Paudel

Ryan³

et al. 2019

Preprint

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“…It forms an 'arginine finger' that directly interacts with AMP-PNP in our structure. Mutation of Arg1162 to glutamine impairs ATP hydrolysis as suggested by biochemical data (Kovač et al, 2018).…”

Section: Cancer-related Chd4 Mutationsmentioning

confidence: 96%

“…Mutations involved in various cancer phenotypes have been observed in the PHD finger 2, the double chromodomain, and both lobes of the ATPase motor. To elucidate effects of such mutations on CHD4 activity, the D. melanogaster CHD4 homologue Mi-2 has been used as a model protein for functional analysis (Kovač et al, 2018). CHD4 mutations have been found to fall in two categories.…”

Section: Cancer-related Chd4 Mutationsmentioning

confidence: 99%

“…Selected sites of mutation are described below. Mutation of residue His1151 to arginine results in a significant reduction of ATPase activity and abolishes chromatin remodelling activity (Kovač et al, 2018). The close proximity of this residue to motif Va (CHD4 residues 1147-1150) makes it likely that the mutation disrupts motif Va function, leading to an uncoupling of the ATPase activity from chromatin remodelling.…”

Section: Cancer-related Chd4 Mutationsmentioning

confidence: 99%

“…Maintenance of the integrity of the nucleosome in the presence of CHD4 is consistent with the role of CHD4 in gene repression, and in heterochromatin formation and maintenance. Finally, the detailed nucleosome-CHD4 structure enables mapping of known human disease mutations (Kovač et al, 2018;Sifrim et al, 2016;Weiss et al, 2016) and indicates how these perturb enzyme function.…”

Section: Introductionmentioning

confidence: 99%

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Nucleosome-CHD4 chromatin remodeller structure explains human disease mutations

Farnung

Ochmann

Cramer

2019

Preprint

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The chromatin remodelling 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 remodelling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our results also rationalize the effect of CHD4 mutations that are associated with cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome.

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Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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2023

Encyclopedia of Life Sciences

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Vital processes such as transcription, repair, replication and recombination continuously shape cellular chromatin landscape. The chromodomain helicase DNA‐binding (CHD) family of enzymes regulate chromatin dynamics by utilising energy from ATP hydrolysis to alter nucleosomal position, structure and composition, thereby modulating accessibility of the underlying DNA sequence. The CHD enzymes are highly conserved in evolution, and genetic studies in fungi, plants and animals demonstrate their critical roles in regulation of cellular identity and fate and organismal development. Advances in genomic studies over the past two decades led to the identification of frequent DNA copy‐number alterations, mutations and aberrant expression of CHDs in human malignancies and various disorders, highlighting their importance as relevant biomarkers or targets for therapeutic intervention. Key Concepts CHD family of enzymes (CHD1‐9) are evolutionary conserved ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes, such as transcription, replication and repair. They are critical for normal organismal development and are frequently mutated in human disorders and cancers. Chromodomain helicase DNA‐binding proteins (CHD1‐9) are evolutionary conserved family of ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes such as transcription, replication and DNA repair. CHD enzymes share a common domain structure: two N‐terminal chromodomains, a central ATPase/helicase domain, and a C‐terminal DNA‐binding domain. CHD proteins play crucial roles in diverse cellular processes, including embryonic development, stem cell maintenance and differentiation, and tissue‐specific gene expression. Dysregulation of CHD proteins has been associated with various human diseases, including cancer and neurodevelopmental disorders. CHD proteins are attractive targets for the development of new therapies for diseases associated with chromatin dysfunction. Understanding the molecular mechanisms underlying the function of CHD proteins may pave the way for the development of new drugs that target these proteins and improve the treatment of a variety of human diseases.

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

Cited by 36 publications

References 63 publications

CHD4 slides nucleosomes by decoupling entry- and exit-side DNA translocation

CHD4 slides nucleosomes by decoupling entry- and exit-side DNA translocation

Nucleosome-CHD4 chromatin remodeller structure explains human disease mutations

Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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