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The ICF syndrome protein CDCA7 harbors a unique DNA binding domain that recognizes a CpG dyad in the context of a non-B DNA.
- Source :
-
Science advances [Sci Adv] 2024 Aug 23; Vol. 10 (34), pp. eadr0036. Date of Electronic Publication: 2024 Aug 23. - Publication Year :
- 2024
-
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.
- Subjects :
- Humans
DNA-Binding Proteins metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins chemistry
Protein Domains
DNA metabolism
Cell Cycle Proteins metabolism
Cell Cycle Proteins genetics
Cell Cycle Proteins chemistry
Mutation
Heterochromatin metabolism
Heterochromatin genetics
Face abnormalities
Nuclear Proteins
Primary Immunodeficiency Diseases metabolism
Primary Immunodeficiency Diseases genetics
DNA Methylation
CpG Islands
Protein Binding
Immunologic Deficiency Syndromes metabolism
Immunologic Deficiency Syndromes genetics
Centromere metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 10
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 39178265
- Full Text :
- https://doi.org/10.1126/sciadv.adr0036