Molecular basis of maintenance DNA methylation

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H04818
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Genetics/Chromosome dynamics
• Research Institution: The University of Tokyo
• Principal Investigator: Nishiyama Atsuya 東京大学, 医科学研究所, 准教授 (50378840)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: DNAメチル化 / DNA複製 / ユビキチン / DNMT1 / UHRF1 / PCNA / PAF15

Outline of Final Research Achievements

DNA methylation is a chemical modification that acts as a "cellular memory" and plays an important role in cell differentiation and suppression of carcinogenesis. DNA methyltransferase 1 (DNMT1) is a DNA methylation enzyme that ensures accurate inheritance of DNA methylation patterns to daughter DNA during chromosome replication. The function of the E3 ubiquitin ligase UHRF1 is also essential for the localization of DNMT1 at DNA methylation sites, but the molecular mechanism is not yet clear. In this study, we identified PAF15 as a novel DNMT1 interacting protein. We then clarified that UHRF1-dependent ubiquitination of PAF 15 controls the localization of DNMT1 at the methylation sites and ensures faithful inheritance of DNA methylation.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

DNAメチル化酵素は抗がん剤の作用点としても注目を集めており、本研究成果はDNAメチル化継承の新たなメカニズムを明らかとした学術的な意義に加えて、DNAメチル化酵素阻害剤の開発推進に大きく寄与する可能性がある。また、PAF15は様々ながん細胞で高発現していることが報告されており、PAF15の高発現がDNAメチル化制御に与える影響を明らかにすることは今後の重要な課題と考えられる。