The essential role of cyclin-dependent kinase CRK9 in trypanosome pre-mRNA processing

细胞周期蛋白依赖性激酶 CRK9 在锥虫前 mRNA 加工中的重要作用

基本信息

  • 批准号:
    10219576
  • 负责人:
  • 金额:
    $ 41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-02 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Summary The kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. affect millions of people worldwide, causing Human African Trypanosomiasis (HAT), Chagas’ disease, and various forms of Leishmaniasis, respectively. Since drugs for these neglected tropical diseases are limited, often toxic and difficult to administer, and parasite resistance to existing drugs is on the rise, it is important to develop new chemo- therapeutic strategies. Our research is focused on trypanosome gene expression because the underlying mechanisms deviate substantially from those in the human host. For example, polycistronic transcription of protein coding genes and processing of pre-mRNA by spliced leader trans splicing are parasite-specific steps in mRNA synthesis and maturation. We discovered in T. brucei that the activity of the cyclin-dependent kinase (CDK) CRK9 is required for trans splicing. By generating a cell line that expresses analog-sensitive CRK9 and no wild-type enzyme, we could chemically inhibit the enzyme in specific manner in cultured cells. Surprisingly, we observed an instant splicing block after applying the inhibitor, suggesting that CRK9 carries out essential reversible phosphorylation on the RNA processing machinery. Our preliminary data indicate that one of CRK9’s substrate is the SR protein and known splicing factor TSR1, and that blocking CRK9 activity affects the assembly of the spliceosome, the large and dynamic RNA-protein complex that carries out the splicing reaction. Consequently, we will determine the mechanism of how CRK9 aids or controls the splicing process. Furthermore, CDKs represent a highly druggable enzyme class, and CRK9 forms an unusual trimeric enzyme complex with a deviant L-type cyclin and a kinetoplastid-specific protein, suggesting that CRK9 is a promising target for chemotherapeutic intervention. Therefore, we propose to characterize the enzyme complex and determine a minimal complex that is active and can be expressed recombinantly as prerequisite for future high throughput inhibitor screens. Finally, based on preliminary data, we will test the hypothesis that CRK9 is the target of the compound SCYX-7158 which is currently in clinical trials against HAT.
总结

项目成果

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ARTHUR GUNZL其他文献

ARTHUR GUNZL的其他文献

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{{ truncateString('ARTHUR GUNZL', 18)}}的其他基金

The essential role of cyclin-dependent kinase CRK9 in trypanosome pre-mRNA processing
细胞周期蛋白依赖性激酶 CRK9 在锥虫前 mRNA 加工中的重要作用
  • 批准号:
    10570982
  • 财政年份:
    2021
  • 资助金额:
    $ 41万
  • 项目类别:
The essential role of cyclin-dependent kinase CRK9 in trypanosome pre-mRNA processing
细胞周期蛋白依赖性激酶 CRK9 在锥虫前 mRNA 加工中的重要作用
  • 批准号:
    10362703
  • 财政年份:
    2021
  • 资助金额:
    $ 41万
  • 项目类别:
RNA polymerase II transcription in trypanosomes
锥虫中的 RNA 聚合酶 II 转录
  • 批准号:
    8190182
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
RNA polymerase II transcription in trypanosomes
锥虫中的 RNA 聚合酶 II 转录
  • 批准号:
    8653521
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
RNA polymerase II transcription in trypanosomes
锥虫中的 RNA 聚合酶 II 转录
  • 批准号:
    8827661
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
Trypanosome class II transcription pre-initiation complex
锥虫 II 类转录前起始复合物
  • 批准号:
    7843594
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
RNA polymerase II transcription in trypanosomes
锥虫中的 RNA 聚合酶 II 转录
  • 批准号:
    8259403
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
RNA polymerase II transcription in trypanosomes
锥虫中的 RNA 聚合酶 II 转录
  • 批准号:
    8447031
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
Trypanosome class II transcription pre-initiation complex
锥虫 II 类转录前起始复合物
  • 批准号:
    7590870
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
Multifunctional class I transcription in T. brucei
布氏锥虫中的多功能 I 类转录
  • 批准号:
    8414838
  • 财政年份:
    2004
  • 资助金额:
    $ 41万
  • 项目类别:

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