Human CHD2 Is a Chromatin Assembly ATPase Regulated by Its Chromo- and DNA-binding Domains

Jessica C Liu,Catarina G Ferreira,Timur Yusufzai

doi:10.1074/jbc.m114.609156

Jessica C Liu, Catarina G Ferreira + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m114.609156

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Abstract

Chromodomain helicase DNA-binding protein 2 (CHD2) is an ATPase and a member of the SNF2-like family of helicase-related enzymes. Although deletions of CHD2 have been linked to developmental defects in mice and epileptic disorders in humans, little is known about its biochemical and cellular activities. In this study, we investigate the ATP-dependent activity of CHD2 and show that CHD2 catalyzes the assembly of chromatin into periodic arrays. We also show that the N-terminal region of CHD2, which contains tandem chromodomains, serves an auto-inhibitory role in both the DNA-binding and ATPase activities of CHD2. While loss of the N-terminal region leads to enhanced chromatin-stimulated ATPase activity, the N-terminal region is required for ATP-dependent chromatin remodeling by CHD2. In contrast, the C-terminal region, which contains a putative DNA-binding domain, selectively senses double-stranded DNA of at least 40 base pairs in length and enhances the ATPase and chromatin remodeling activities of CHD2. Our study shows that the accessory domains of CHD2 play central roles in both regulating the ATPase domain and conferring selectivity to chromatin substrates.

Highlights

Chromodomain helicase DNA-binding protein 2 (CHD2) is a conserved ATPase and deletions of CHD2 have been linked to developmental and neurological disorders
Because CHD2 contains tandem chromodomains, which are predicted to interact with histones [17], and a putative DNA-binding domain [6], we measured the effects of adding core histones, plasmid DNA, or pre-assembled, saltdialyzed chromatin on the ATPase activity of CHD2
We found that wild-type CHD2 (WT) CHD2 exhibits nearly undetectable ATPase activity alone (Basal) or in the presence of core histones (Histones; Fig. 1D)

Summary

Background

CHD2 is a conserved ATPase and deletions of CHD2 have been linked to developmental and neurological disorders. Chromodomain helicase DNA-binding protein 2 (CHD2) is an ATPase and a member of the SNF2-like family of helicaserelated enzymes. Deletions of CHD2 have been linked to developmental defects in mice and epileptic disorders in humans, little is known about its biochemical and cellular activities. We investigate the ATP-dependent activity of CHD2 and show that CHD2 catalyzes the assembly of chromatin into periodic arrays. The C-terminal region, which contains a putative DNA-binding domain, selectively senses double-stranded DNA of at least 40 base pairs in length and enhances the ATPase and chromatin remodeling activities of CHD2. Chromodomain helicase DNA-binding protein 2 (CHD2) is a member of the SNF2-like family of helicase-related enzymes, which includes all known ATP-dependent chromatin remodeling factors [1,2,3]. ISWI and CHD1 can catalyze the assembly of periodic

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EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION