Oncotarget

Research Papers:

Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription

Zhihui Liu _, Norris Lam and Carol J. Thiele

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Oncotarget. 2015; 6:27628-27640. https://doi.org/10.18632/oncotarget.4733

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Abstract

Zhihui Liu1, Norris Lam1, Carol J. Thiele1

1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA

Correspondence to:

Zhihui Liu, e-mail: liuzhihu@mail.nih.gov

Keywords: CASZ1, tumor suppressor, NuRD complex, DNA repair protein, cofactors

Received: March 16, 2015     Accepted: July 27, 2015     Published: August 07, 2015

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.


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