Mechanisms underlying maintenance of genome integrity by DNA methylation

2023 Fiscal Year Final Research Report

• Project Area: Mechanisms underlying replication of non-genomic codes that mediate plasticity and robustness for cellular inheritance
• Project/Area Number: 19H05740
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: Nakanishi Makoto 東京大学, 医科学研究所, 教授 (40217774)
• Co-Investigator(Kenkyū-buntansha): 藤 泰子 東京工業大学, 生命理工学院, 准教授 (10623978) ; 鵜木 元香 東京大学, 大学院医学系研究科(医学部), 准教授 (30525374)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Keywords: DNAメチル化 / DNMT1 / 複製 / ICF症候群 / 岡崎フラグメント

Outline of Final Research Achievements

Nakanishi revealed the molecular mechanisms of DNA maintenance methylation. He also revealed the molecular structural basis of UHRF1 inhibition by mDPPA3. He found that CDCA7 could bind specifically to hemimethylated DNA on nucleosomes and succeeded in clarifying the details of its binding structural mode. He also reported that histone H3 ADP ribosylation by the PARP1/HPF1 complex is LIG3-dependent. Unoki identified a role for CDCA7 and HELLS in ICF syndrome. Fuji discovered a novel plant-specific non-CpG methylation mechanism.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

世界で初めてDNA維持メチル化機構の全貌を明らかにしたことは学術的意義が非常に深い。またDNA維持メチル化機構の解明は、老化やその他ヒト疾患の理解にも繋がることからその社会的意義も深い。実際、鵜木によるCDCA7A/HELLSによるDNA維持メチル化機構の解析は、ヒトのICF症候群の理解に強く結びついた。藤の見出した植物特異的非CpGメチル化の分子基盤の解明は、今後哺乳動物細胞におけるDNAメチル化機構の解明に有用と考えられ、その学術的意義は高い。