Abstract
NuRD (nucleosome remodeling and histone deacetylase) is a versatile multi-protein complex with roles intranscription regulation and the DNA damage response. Here, we show that ZMYND8 bridges NuRD to a number of putative DNA-binding zinc finger proteins. The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A. Both GATAD2A and GATAD2B exclusively form homodimers and define mutually exclusive NuRD subcomplexes. ZMYND8 and NuRD share a large number of genome-wide bindingsites, mostly active promoters and enhancers. Depletion of ZMYND8 does not affect NuRD occupancy genome-wide and only slightly affects expression of NuRD/ZMYND8 target genes. In contrast, theMYND domain in ZMYND8 facilitates the rapid,poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to sites of DNA damage to promote repair by homologous recombination. Thus, these results show that a specific substoichiometric interaction with a NuRD subunit paralogue provides unique functionality to distinct NuRD subcomplexes.
Highlights
The nucleosome remodeling and histone deacetylase (NuRD) complex is a highly conserved chromatin-remodeling complex that is generally associated with transcriptional repression (Allen et al, 2013)
ZMYND8 Connects the NuRD Complex to the Z3 Module via Its MYND Domain Recently, ZMYND8 was identified as a novel interactor of the NuRD complex (Eberl et al, 2013; Malovannaya et al, 2011; Smits et al, 2013)
The MBD2- and MBD3-GFP purifications were significantly enriched for NuRD core subunits (Figure 1A; Figure S1A), some zinc fingers (ZNFs) proteins, ZMYND8, and the known NuRD interactor SALL4
Summary
The nucleosome remodeling and histone deacetylase (NuRD) complex is a highly conserved chromatin-remodeling complex that is generally associated with transcriptional repression (Allen et al, 2013). The NuRD complex contains two catalytic activities: the ATP-dependent chromatin-remodeling enzymes CHD3, CHD4, and CHD5 (Allen et al, 2013; Potts et al, 2011) and the histone deacetylases HDAC1 and HDAC2. ZMYND8 has a completely different domain architecture consisting of a PHD finger, BROMO domain, and PWWP domain at its N terminus and a MYND domain located close to its C terminus This protein is called protein-kinase-C-binding protein (PKCBP1) or RACK7 (Ansieau and Sergeant, 2003; Fossey et al, 2000). The BROMO domain of ZMYND8 has been linked to transcriptional repression in response to DNA double-strand breaks (DSBs) (Gong et al, 2015)
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