Student and Faculty Publications
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
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Genetic Processes Commons, Medical Genetics Commons, Oncology Commons
Comments
Supplementary Materials
PMID: 39178265