Structural basis for activation of DNMT1

Amika Kikuchi, Hiroki Onoda, Kosuke Yamaguchi, Satomi Kori, Shun Matsuzawa, Yoshie Chiba, Shota Tanimoto, Sae Yoshimi, Hiroki Sato, Atsushi Yamagata, Mikako Shirouzu, Naruhiko Adachi, Jafar Sharif, Haruhiko Koseki, Atsuya Nishiyama, Makoto Nakanishi, Pierre-Antoine Defossez and Kyohei Arita ()
Additional contact information
Amika Kikuchi: Yokohama City University, Tsurumi-ku
Hiroki Onoda: Yokohama City University, Tsurumi-ku
Kosuke Yamaguchi: Université Paris Cité, CNRS, Epigenetics and Cell Fate
Satomi Kori: Yokohama City University, Tsurumi-ku
Shun Matsuzawa: Yokohama City University, Tsurumi-ku
Yoshie Chiba: The University of Tokyo
Shota Tanimoto: The University of Tokyo
Sae Yoshimi: Yokohama City University, Tsurumi-ku
Hiroki Sato: Yokohama City University, Tsurumi-ku
Atsushi Yamagata: RIKEN Center for Biosystems Dynamics Research
Mikako Shirouzu: RIKEN Center for Biosystems Dynamics Research
Naruhiko Adachi: High Energy Accelerator Research Organization (KEK)
Jafar Sharif: RIKEN Center for Integrative Medical Sciences (IMS)
Haruhiko Koseki: RIKEN Center for Integrative Medical Sciences (IMS)
Atsuya Nishiyama: The University of Tokyo
Makoto Nakanishi: The University of Tokyo
Pierre-Antoine Defossez: Université Paris Cité, CNRS, Epigenetics and Cell Fate
Kyohei Arita: Yokohama City University, Tsurumi-ku

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34779-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34779-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34779-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().