DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation.

ABSTRACT: DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation

SUBMITTER: Adam S 

PROVIDER: S-EPMC7381644 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature