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Structural basis of specific DNA binding by the transcription factor ZBTB24

Journal Article · · Nucleic Acids Research
DOI:https://doi.org/10.1093/nar/gkz557· OSTI ID:1591896
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [1];  [2];  [2]
  1. Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  2. Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States); Univ. of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX (United States)
  3. Univ. of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX (United States)
  4. Emory Univ. School of Medicine, Atlanta, GA (United States)
+ Show Author Affiliations
ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes—the other three being DNMT3B, CDCA7 and HELLS—that are mutated in immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here, we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome. The sequence is present at multiple loci, including the Cdca7 promoter region, and ZBTB24 binding is mostly associated with gene activation. Crystallography and DNA-binding data revealed that the last four of the eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 confer specificity of DNA binding. Two ICF missense mutations have been identified in the ZBTB24 ZF domain, which alter zinc-binding cysteine residues. We demonstrated that the corresponding C382Y and C407G mutations in mouse ZBTB24 abolish specific DNA binding and fail to induce Cdca7 expression. Our analyses indicate and suggest a structural basis for the sequence specific recognition by a transcription factor centrally important for the pathogenesis of ICF syndrome.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
U.S. National Inst. of Health (NIH); Cancer Prevention and Research Inst. of Texas
OSTI ID:
1591896
Journal Information:
Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 16 Vol. 47; ISSN 0305-1048
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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  • Libraries, The University of North Carolina at Chapel Hill University
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/wcvb-k036
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Cited By (5)

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome journal August 2020
Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease journal January 2020
The ZBTB24-CDCA7 axis regulates HELLS enrichment at centromeric satellite repeats to facilitate DNA methylation journal January 2020
DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome journal November 2019
Identification of ZBTB24 protein domains and motifs for heterochromatin localization and transcriptional activation journal October 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Chromatin and Epigenetics
Gene Regulation