Structural basis for activation of DNMT1

Nat Commun. 2022 Nov 21;13(1):7130. doi: 10.1038/s41467-022-34779-4.


DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA (Cytosine-5-)-Methyltransferases* / metabolism
  • DNA / metabolism
  • DNA Methylation
  • Histones* / metabolism
  • Humans
  • Ubiquitin / metabolism


  • DNA
  • DNA (Cytosine-5-)-Methyltransferases
  • Histones
  • Ubiquitin
  • DNMT1 protein, human