So close yet so far apart: distinct flanking sequence recognition by DNMT3A and DNMT3B.

ABSTRACT: DNMT3A and DNMT3B are closely related DNA methyltransferases that catalyze de novo CpG methylation and have distinct preferences for flanking sequences. Despite sharing 91% sequence similarity within their catalytic domains, these paralogs show non-overlapping genomic targeting and divergent biological roles. To uncover the mechanistic basis of this specificity, we performed 16µs of all-atom molecular dynamics simulations on DNMT3A and DNMT3B complexes bound to CpG substrates with varied +2 flanking bases (i.e., CGX). To resolve their base- and shape-readout mechanisms at atomistic detail, we introduced a Comparative Dynamics Analysis (CDA) framework. Our CDA approach revealed that DNMT3A relies on a rigid, sequence-specific hydrogen bonding network and shape-constrained electrostatic anch

SUBMITTER: Barlas AB 

PROVIDER: S-EPMC12350793 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature