DNA-Binding Proteins From MBD Through ZF to BEN: Recognition of Cytosine Methylation Status by One Arginine With Two Conformations

Authors

Xing Zhang
Robert M Blumenthal
Xiaodong Cheng

Publication Date

10-28-2024

Abstract

Maintenance methylation, of palindromic CpG dinucleotides at DNA replication forks, is crucial for the faithful mitotic inheritance of genomic 5-methylcytosine (5mC) methylation patterns. MBD proteins use two arginine residues to recognize symmetrically-positioned methyl groups in fully-methylated 5mCpG/5mCpG and 5mCpA/TpG dinucleotides. In contrast, C2H2 zinc finger (ZF) proteins recognize CpG and CpA, whether methylated or not, within longer specific sequences in a site- and strand-specific manner. Unmethylated CpG sites, often within CpG island (CGI) promoters, need protection by protein factors to maintain their hypomethylated status. Members of the BEN domain proteins bind CGCG or CACG elements within CGIs to regulate gene expression. Despite their overall structural diversity, MBD, ZF and BEN proteins all use arginine residues to recognize guanine, adopting either a 'straight-on' or 'oblique' conformation. The straight-on conformation accommodates a methyl group in the (5mC/T)pG dinucleotide, while the oblique conformation can clash with the methyl group of 5mC, leading to preferential binding of unmethylated sequences.

Keywords

Arginine, DNA Methylation, DNA-Binding Proteins, Humans, CpG Islands, Cytosine, Zinc Fingers, 5-Methylcytosine, Protein Binding, Models, Molecular, DNA, Protein Conformation

DOI

10.1093/nar/gkae832

PMID

39329271

PMCID

PMC11514455

PubMedCentral® Posted Date

10-28-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes