Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

Atsuya Nishiyama (), Christopher B. Mulholland, Sebastian Bultmann, Satomi Kori, Akinori Endo, Yasushi Saeki, Weihua Qin, Carina Trummer, Yoshie Chiba, Haruka Yokoyama, Soichiro Kumamoto, Toru Kawakami, Hironobu Hojo, Genta Nagae, Hiroyuki Aburatani, Keiji Tanaka, Kyohei Arita (), Heinrich Leonhardt () and Makoto Nakanishi ()
Additional contact information
Atsuya Nishiyama: The University of Tokyo
Christopher B. Mulholland: Ludwig-Maximilians-Universität München
Sebastian Bultmann: Ludwig-Maximilians-Universität München
Satomi Kori: Yokohama City University
Akinori Endo: Tokyo Metropolitan Institute of Medical Science
Yasushi Saeki: Tokyo Metropolitan Institute of Medical Science
Weihua Qin: Ludwig-Maximilians-Universität München
Carina Trummer: Ludwig-Maximilians-Universität München
Yoshie Chiba: The University of Tokyo
Haruka Yokoyama: Yokohama City University
Soichiro Kumamoto: The University of Tokyo
Toru Kawakami: Osaka University
Hironobu Hojo: Osaka University
Genta Nagae: University of Tokyo
Hiroyuki Aburatani: University of Tokyo
Keiji Tanaka: Tokyo Metropolitan Institute of Medical Science
Kyohei Arita: Yokohama City University
Heinrich Leonhardt: Ludwig-Maximilians-Universität München
Makoto Nakanishi: The University of Tokyo

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.

Date: 2020
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DOI: 10.1038/s41467-020-15006-4

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