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; Kyohei Arita

doi:10.1038/s41467-022-34779-4

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, Kyohei Arita

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	7130
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34779-4
Publication status	Published - 1 Dec 2022
Externally published	Yes

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Kikuchi, A., Onoda, H., Yamaguchi, K., Kori, S., Matsuzawa, S., Chiba, Y., Tanimoto, S., Yoshimi, S., Sato, H., Yamagata, A., Shirouzu, M., Adachi, N., Sharif, J., Koseki, H., Nishiyama, A., Nakanishi, M., Defossez, P. A., & Arita, K. (2022). Structural basis for activation of DNMT1. Nature Communications, 13(1), Article 7130. https://doi.org/10.1038/s41467-022-34779-4

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title = "Structural basis for activation of DNMT1",

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.",

author = "Amika Kikuchi and Hiroki Onoda and Kosuke Yamaguchi and Satomi Kori and Shun Matsuzawa and Yoshie Chiba and Shota Tanimoto and Sae Yoshimi and Hiroki Sato and Atsushi Yamagata and Mikako Shirouzu and Naruhiko Adachi and Jafar Sharif and Haruhiko Koseki and Atsuya Nishiyama and Makoto Nakanishi and Defossez, \{Pierre Antoine\} and Kyohei Arita",

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AU - Kikuchi, Amika

AU - Onoda, Hiroki

AU - Yamaguchi, Kosuke

AU - Kori, Satomi

AU - Matsuzawa, Shun

AU - Chiba, Yoshie

AU - Tanimoto, Shota

AU - Yoshimi, Sae

AU - Sato, Hiroki

AU - Yamagata, Atsushi

AU - Shirouzu, Mikako

AU - Adachi, Naruhiko

AU - Sharif, Jafar

AU - Koseki, Haruhiko

AU - Nishiyama, Atsuya

AU - Nakanishi, Makoto

AU - Defossez, Pierre Antoine

AU - Arita, Kyohei

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-022-34779-4

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SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7130

ER -

Structural basis for activation of DNMT1

Abstract

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