Structural basis for establishment and maintenance of DNA methylation and histone H3K9me3

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: 19H05741
• 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: Yokohama City University
• Principal Investigator: Arita Kyohei 横浜市立大学, 生命医科学研究科, 教授 (40549648)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Keywords: 構造生物学 / DNA維持メチル化 / UHRF1 / DNMT1 / DPPA3 / 非ゲノム情報複製 / cryo-EM / X線結晶構造解析

Outline of Final Research Achievements

The aim of this study was to establish a structural basis for the replication of non-genome, especially DNA methylation and H3K9me3. Regarding H3K9me3, we established the preparation of ubiquitinated SETDB1, which is an enzymatically activated form. Cryo-EM analysis revealed a novel activation mechanism of the maintenance methyltransferase DNMT1 in DNA maintenance methylation. The structural basis for the inhibition of UHRF1 function by the maternal factor DPPA3 was elucidated using solution NMR. As a developmental study, a combination of computational science and structural biology was used to search for functional inhibitors of UHRF1, and compounds that inhibit binding to LIG1 were successfully identified. These findings led to the proposal of a novel regulatory mechanism for replication of the non-genome.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、非ゲノム情報であるDNAメチル化の維持機構を構造生物学的に明らかにして、DNAメチル化が個体の生涯を通して維持される生物学的に重要な分子機構の理解につながった。また、DNAメチル化の異常がもたらすがんの薬剤開発に向けて、DNA維持メチル化因子UHRF1の機能阻害剤の探索に成功した。今後の抗がん剤開発につながる研究成果を得た。