SNAP-annotated 5mC-DNA-protein interactions: PDB entry 8tlk

PDB-id

8tlk; DSSR-derived features in text and JSON formats; DNAproDB

Class

DNA binding protein-DNA

Method

X-ray (2.99 Å)

Summary

Cdca7 (human) binds non-b-form 32-mer DNA oligo containing a 5mc

Reference

Hardikar S, Ren R, Ying Z, Horton JR, Bramble MD, Liu B, Lu Y, Liu B, Dan J, Zhang X, Cheng X, Chen T (2023): "The ICF syndrome protein CDCA7 harbors a unique DNA-binding domain that recognizes a CpG dyad in the context of a non-B DNA." Biorxiv. doi: 10.1101/2023.12.15.571946.

Abstract

<i>CDCA7</i> , encoding a protein with a C-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.

• The contacts include paired nucleotides (mostly a G in Watson-Crick G-C pairing) and amino-acids within a 4.5-Å distance cutoff to base atoms of 5mC.
• The structure is oriented in the base reference frame of 5mC, allowing for easy comparison and direct superimposition between entries.
• The black sphere (•) denotes the 5-methyl carbon atom in 5mC.