The Icf Syndrome Protein CDCA7 Harbors a Unique DNA Binding Domain That Recognizes a CpG Dyad in the Context of a Non-B DNA

Authors

Swanand Hardikar
Ren Ren
Zhengzhou Ying
Jujun Zhou
John R Horton
Matthew D Bramble
Bin Liu
Yue Lu
Bigang Liu
Luis Della Coletta
Jianjun Shen
Jiameng Dan
Xing Zhang
Xiaodong Cheng
Taiping Chen

Publication Date

8-23-2024

Journal

Science Advances

Abstract

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout the genome. At S phase, CDCA7, but not ICF mutants, is concentrated in constitutive heterochromatin foci, and the formation of such foci can be inhibited by exogenous hemi-methylated non-B DNA bound by the CRD. Binding of the non-B DNA formed in juxtacentromeric regions during DNA replication provides a mechanism by which CDCA7 controls the specificity of DNA methylation.

Keywords

Humans, Primary Immunodeficiency Diseases, DNA Methylation, CpG Islands, Protein Binding, Immunologic Deficiency Syndromes, Centromere, DNA-Binding Proteins, Protein Domains, DNA, Cell Cycle Proteins, Mutation, Heterochromatin, Face, Nuclear Proteins

Comments

Supplementary Materials

PMID: 39178265