title: ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage.
abstract: NuRD (nucleosome remodeling and histone deacetylase) is a versatile multi-protein complex with roles in transcription 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 binding sites, 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, the MYND 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.
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Cornelia G
authors.initials: CG
authors.lastname: Spruijt
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
authors.forename: Martijn S
authors.initials: MS
authors.lastname: Luijsterburg
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Roberta
authors.initials: R
authors.lastname: Menafra
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Rik G H
authors.initials: RG
authors.lastname: Lindeboom
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Pascal W T C
authors.initials: PW
authors.lastname: Jansen
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Raghu Ram
authors.initials: RR
authors.lastname: Edupuganti
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Marijke P
authors.initials: MP
authors.lastname: Baltissen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Wiegant
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Moritz C
authors.initials: MC
authors.lastname: Voelker-Albert
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands.
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Anneloes
authors.initials: A
authors.lastname: Mensinga
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Harmjan R
authors.initials: HR
authors.lastname: Vos
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands. Electronic address: h.stunnenberg@ncmls.ru.nl.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands. Electronic address: h.van.attikum@lumc.nl.
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, the Netherlands. Electronic address: michiel.vermeulen@science.ru.nl.
authors.forename: Michiel
authors.initials: M
authors.lastname: Vermeulen
mesh_terms: D000595:Amino Acid Sequence; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050980:GATA Transcription Factors / Q000378:metabolism*; D015894:Genome, Human; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000072417:Protein Domains; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050980:GATA Transcription Factors; C468769:GATAD2A protein, human; D021122:Protein Subunits; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C000617312:ZMYND8 protein, human; D011064:Poly Adenosine Diphosphate Ribose; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
keywords: DNA damage; GATAD2A; NuRD; ZMYND8; chromatin; gene expression; interaction proteomics; next-generation sequencing