Medical Institute of Bioregulation, Kyushu University

[Seminar in English]

Title

Genetic and structural investigations of DNA methylation maintenance mechanisms

Speaker

Prof. Pierre-Antoine Defossez
Epigenetics and Cell Fate, University Paris Diderot

Date

Dec. 9 (Mon), 2019
16：40〜17：20

Venue

Lecture Room 102, 1F, Biomedical Research Station, Hospital Campus
No.33 on the following linked map.
（https://www.kyushu-u.ac.jp/f/35768/2019hospital-en_2.pdf）

Abstract

DNA methylation is an essential epigenetic mark in mammals, and it needs to be maintained at each round of DNA replication. Two key actors in this epigenetic maintenance process are the DNA methyltransferase DNMT1, and an E3 ubiquitin ligase acting upstream of DNMT1, called UHRF1. How UHRF1 itself is recruited to replicating chromatin is incompletely understood. One of the mechanisms that was put forward is an interaction between the Tandem Tudor Domain (TTD) of UHRF1 and histone H3K9me2/3. Recently, we identified a new and unexpected mechanism that directly couples DNA replication and UHRF1 recruitment: a methylated histone-like region of DNA Ligase 1 (LIG1K126me2/me3) binds the UHRF1 TTD with nanomolar affinity, permitting UHRF1 recruitment to chromatin. We will report our recently obtained structure of the LIG1/UHRF1 complex, which sheds light on its regulation. We will also report on our unbiased CRISPR screen aimed at identifying new factors involved in DNA methylation maintenance.

References

1. Cornett EM, Ferry L, Defossez PA, Rothbart SB.
   Lysine Methylation Regulators Moonlighting outside the Epigenome.
   Mol Cell. 2019 Sep 19;75(6):1092-1101.
2. Kori S, Ferry L, Matano S, Jimenji T, Kodera N, Tsusaka T, Matsumura R, Oda T, Sato M, Dohmae N, Ando T, Shinkai Y, Defossez PA*, Arita K*.
   Structure of the UHRF1 Tandem Tudor Domain Bound to a Methylated Non-histone Protein, LIG1, Reveals Rules for Binding and Regulation.
   Structure. 2019 Mar 5;27(3):485-496.e7.
3. Ferry L, Fournier A, Tsusaka T, Adelmant G, Shimazu T, Matano S, Kirsh O, Amouroux R, Dohmae N, Suzuki T, Filion GJ, Deng W, de Dieuleveult M, Fritsch L, Kudithipudi S, Jeltsch A, Leonhardt H, Hajkova P, Marto JA, Arita K, Shinkai Y*, Defossez PA*.
   Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.
   Mol Cell. 2017 Aug 17;67(4):550-565.e5.

Contact

Division of Epigenomics and Development, Medical Institute of Bioregulation
Motoko UNOKI
TEL: 092 (642) 6761