title: Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription.
abstract: The zinc finger transcription factor CASZ1 has been found to control neural fate-determination in flies, regulate murine and frog cardiac development, control murine retinal cell progenitor expansion and function as a tumor suppressor gene in humans. However, the molecular mechanism by which CASZ1 regulates gene transcription to exert these diverse biological functions has not been described. Here we identify co-factors that are recruited by CASZ1b to regulate gene transcription using co-immunoprecipitation (co-IP) and mass spectrometry assays. We find that CASZ1b binds to the nucleosome remodeling and histone deacetylase (NuRD) complex, histones and DNA repair proteins. Mutagenesis of the CASZ1b protein assay demonstrates that the N-terminus of CASZ1b is required for NuRD binding, and a poly(ADP-ribose) binding motif in the CASZ1b protein is required for histone H3 and DNA repair proteins binding. The N-terminus of CASZ1b fused to an artificial DNA-binding domain (GAL4DBD) causes a significant repression of transcription (5xUAS-luciferase assay), which could be blocked by treatment with an HDAC inhibitor. Realtime PCR results show that the transcriptional activity of CASZ1b mutants that abrogate NuRD or histone H3/DNA binding is significantly decreased. This indicates a model in which CASZ1b binds to chromatin and recruits NuRD complexes to orchestrate epigenetic-mediated transcriptional programs.
authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Zhihui
authors: Z
authors: Liu
authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Norris
authors: N
authors: Lam
authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Carol J
authors: CJ
authors: Thiele
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D009707:Nucleosomes / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: C511127:CASZ1 protein, human; C000600132:CASZ1 protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
keywords: CASZ1; DNA repair protein; NuRD complex; cofactors; tumor suppressor