The role of DNA replication machinery in maintenance of DNA methylation

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790290
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Nagoya City University
• Principal Investigator: NISHIYAMA Atsuya 名古屋市立大学, 医学(系)研究科(研究院), 講師 (50378840)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: DNAメチル化 / ユビキチン化 / DNA複製 / 試験管内系 / クロマチン

Research Abstract

Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. However, it is unclear how the maintenance of DNA methylation and DNA replication is coordinated. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. We found that Uhrf1 has an activity to ubiquitylate histone H3. Dnmt1, which converts hemi-methyl DNA to full-methyl DNA, preferentially associates with ubiquitylated histone H3 in vitro through a region previously identified as a replication foci targeting sequence. We also show that ubiquitin ligase activity of Uhrf1 is essential for Dnmt1 recruitment to DNA replication sites and maintaining DNA methylation in mammalian cultured cells. Our finding represent the first evidence of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.

Research Products

• [Journal Article] Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication (2013)
  • Author(s): Atsuya Nishiyama, Luna Yamaguchi, Jafar Sharif, Yoshikazu Johmura, Takeshi Kawamura, Keiko Nakanishi, Shintaro Shimamura, Kyohei Arita, Tatsuhiko Kodama, Fuyuki Ishikawa, Haruhiko Koseki, and Makoto Nakanishi
  • Journal Title: Nature Volume: 502(7470) Pages: 249-253
  • DOI: 10.1038/nature12488
  • Peer Reviewed
• [Presentation] Regulation of DNA methylation-coupled histone H3 ubiquitylation (2014)
  • Author(s): Atsuya Nishiyama, Luna Yamaguchi, and Makoto Nakanishi
  • Organizer: Replication, repair and transcription; coupling mechanisms and chromatin dynamics for genome integrity
  • Place of Presentation: 京都
  • Year and Date: 2014-02-05
• [Presentation] Uhrf1依存的なヒストンH3のユビキチン化を介したDNA維持メチル化制御機構 (2013)
  • Author(s): 西山敦哉, 山口留奈, Jafar Sharif, 城村由和, 川村猛, 中西圭子, 島村真太郎, 有田恭平, 児玉龍彦, 石川冬木, 古関明彦, 中西真
  • Organizer: 第36回分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-06
• [Presentation] ヒストンH3のユビキチン化とDNA維持メチル化制御 (2013)
  • Author(s): 西山敦哉
  • Organizer: 平成25年度遺伝研研究会 「クロマチンによる遺伝情報のエピジェネティック制御機構」
  • Place of Presentation: 三島
  • Year and Date: 2013-10-18
• [Presentation] Uhrf1依存的なPCNAのモノユビキチン化を介したTLSポリメラーゼとDNA維持メチル化の関わり (2012)
  • Author(s): 山口留奈, 西山敦哉, 城村由和, 島村真太郎, 石川冬木, 秋山昌広, 真木寿治, 中西真
  • Organizer: 第35回分子生物学会年会
  • Place of Presentation: 博多
  • Year and Date: 2012-12-11
• [Presentation] ヒストンH3のユビキチン化を介したDNA維持メチル化の監視機構 (2012)
  • Author(s): 西山敦哉, 山口留奈, 城村由和, 島村真太郎, 石川冬木, 川村猛, Jafar Sharif, 古関明彦, 中西真
  • Organizer: 第35回分子生物学会年会
  • Place of Presentation: 博多
  • Year and Date: 2012-12-11
• [Presentation] Implication of TLS in maintaining genome integrity under defective maintenance DNA methylation through Uhrf1-dependent PCNA ubiquitylation (2012)
  • Author(s): Yamaguchi L, Nishiyama A, Johmura Y, Shimamura S, Ishikawa F, Hanaoka F, and Nakanishi M
  • Organizer: The 8^<th> 3R Symposium
  • Place of Presentation: 淡路
  • Year and Date: 2012-11-25
• [Presentation] Uhrf1-mediated histone H3 ubiquitylation couples DNA methylation with DNA replication (2012)
  • Author(s): Nishiyama A, Yamaguhi L, Johmura Y, Shimamura S, Ishikawa F, Sharif J, Koseki H, and Nakanishi M
  • Organizer: The 8^<th> 3R Symposium
  • Place of Presentation: 淡路
  • Year and Date: 2012-11-25
• [Book] エピジェネティクスキーワード事典 (2013)
  • Author(s): 西山敦哉, 山口留奈, 中西真
  • Total Pages: 67-72
  • Publisher: 羊土社