Elucidation of the intron recognition mechanism by U2AF1

• Project/Area Number: 18K06086
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Shimane University
• Principal Investigator: Obayashi Eiji 島根大学, 学術研究院医学・看護学系, 准教授 (50321740)
• Co-Investigator(Kenkyū-buntansha): 浦野 健 島根大学, 学術研究院医学・看護学系, 教授 (70293701)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RNAスプライシング / 立体構造解析 / X線結晶構造解析

Outline of Final Research Achievements

The accurate exclusion of introns by RNA splicing is critical for the production of mature mRNA. U2AF1 binds specifically to the 3’ splice site, which includes an essential AG dinucleotide. Even a single amino acid mutation of U2AF1 can cause serious disease such as certain cancers or myelodysplastic syndromes. Here, we describe the first crystal structures of wild-type and pathogenic mutant U2AF1 complexed with target RNA, revealing the mechanism of 3’ splice site selection, and how aberrant splicing results from clinically important mutations. Unexpected features of this mechanism may assist the future development of new treatments against diseases caused by splicing errors.

Academic Significance and Societal Importance of the Research Achievements

本研究では、近年報告が多い、がんや血液学的悪性疾患の患者に見られるU2AF1タンパク質のアミノ酸変異について、そのRNAスプライシング異常を引き起こす仕組みを明らかにした。この結果は、スプライシング異常により引き起こされる様々な病気の診断・治療法開発に向けた画期的な成果であり、この成果は、『Nature Communications』に掲載された。がんや血液学的悪性疾患は年齢とともに発症率が増加するため、今後の高齢化社会の進展により患者数のさらなる増加が容易に予想される。特に高齢者率が日本一の島根県において対策は急務であり、その意義は大きい。

Research Products

• [Journal Article] Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1 (2020)
  • Author(s): Yoshida Hisashi、Park Sam-Yong、Sakashita Gyosuke、Nariai Yuko、Kuwasako Kanako、Muto Yutaka、Urano Takeshi、Obayashi Eiji
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 4744-4752
  • DOI: 10.1038/s41467-020-18559-6
  • Peer Reviewed / Open Access
• [Journal Article] Nucleus Accumbens-Associated Protein 1 Binds DNA Directly through the BEN Domain in a Sequence-Specific Manner (2020)
  • Author(s): Nakayama Naomi、Sakashita Gyosuke、Nagata Takashi、Kobayashi Naohiro、Yoshida Hisashi、Park Sam-Yong、Nariai Yuko、Kato Hiroaki、Obayashi Eiji、Nakayama Kentaro、Kyo Satoru、Urano Takeshi
  • Journal Title: Biomedicines Volume: 8 Issue: 12 Pages: 608-608
  • DOI: 10.3390/biomedicines8120608
  • Peer Reviewed / Open Access
• [Journal Article] Generation and characterization of antagonistic anti-human interleukin (IL)-18 monoclonal antibodies with high affinity: Two types of monoclonal antibodies against full-length IL-18 and the neoepitope of inflammatory caspase-cleaved active IL-18. (2019)
  • Author(s): Nariai Y, Kamino H, Obayashi E, Kato H, Sakashita G, Sugiura T, Migita K, Koga T, Kawakami A, Sakamoto K, Kadomatsu K, Nakakido M, Tsumoto K, Urano T.
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 663 Pages: 71-82
  • DOI: 10.1016/j.abb.2019.01.001
  • Peer Reviewed / Open Access