2022 Fiscal Year Final Research Report
Study of splicing factor ZRSR1 in spermatogenesis for therapeutic application
| Project/Area Number |
20K06448
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 42030:Animal life science-related
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| Research Institution | Yokohama City University (2021-2022)
Nippon Medical School (2020) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
浜窪 隆雄 日本医科大学, 先端医学研究所, 教授 (90198797)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | RNAスプライシング / minor spliceosome / ZRSR2 / exon definition / プロテオミクス / Targeted proteomics |
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| Outline of Final Research Achievements |
ZRSR1/2 have been implicated in 3’ splice site recognition of U12 introns, a rare group of introns (approximately 0.5% in humans) . Our previous study using Zrsr1 mutant mice revealed that increased U12 intron retention inhibited adjacent U2 intron splicing, suggesting mutual influences between neighboring U12 and U2 introns. To further understand the interplay between U2 and U12 intron splicing, we generated a minigene containing U12 intron 5 flanked by U2 introns 4 and 6 of the Rfx5 gene. Minigene analysis showed that 1. U12 intron represses the efficiency of upstream U2 intron splicing, 2. the upstream U2 intron promotes the U12 intron splicing, 3. deletion of 5’ss of U12 intron increased the efficiency of the upstream U2 intron splicing, suggesting an interaction of 5’ss of U12 intron with major spliceosome enhances U12 intron splicing. Proteomic analysis of Zrsr1-interacting proteins identified candidates for exon definition components between minor and major spliceosomes.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、Zrsr1変異マウスの解析、分子生物学的、生化学的解析からminor spliceosomeとmajor spliceosome間の相互作用を明らかにし、この相互作用がU12イントロンスプライシング を促進していることを示した。Zrsr1変異マウスは精子形成不全を示し、ZRSR1のパラログであるZRSR2の変異は骨髄異形成症候群の発症と関連することが報告されており、本研究の成果はZRSR1/2によるU12イントロンのスプライシング促進による治療の可能性を持っており、社会的意義が高い。
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