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Regulation of cell cycle transitions by cyclin-dependent kinase in trypanosomes

锥虫中细胞周期蛋白依赖性激酶对细胞周期转变的调节

基本信息

批准号：
10362149
负责人：
Ziyin Li
金额：
$ 46.74万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-13 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362149
关键词：
African Trypanosomiasis Anaphase Aneuploidy Binding Biochemical Biological Cell Cycle Cell Cycle Checkpoint Cell Cycle Proteins Cell Cycle Regulation Cell Cycle Stage Cell Death Cell division Cells Chromosome Segregation Complex Cyclin-Dependent Kinases Cytokinesis DNA Damage Disease Ensure Eukaryota Foundations Funding G1/S Transition G2/M Transition Genome Genomics Human Insecta Intervention Investigation Kinetochores Lead Maintenance Mediating Metaphase Microtubules Mitosis Mitotic Molecular Monitor Names Nuclear Accidents Organism Outcome Outcome Study Parasites Parasitic Diseases Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Proteins Publishing Regulation Regulatory Pathway Role S phase Series System Testing Time Trypanosoma Trypanosoma brucei brucei Trypanosomiasis Work Yeasts base chemotherapy drug development event cycle experimental study genetic regulatory protein genome integrity new therapeutic target novel premature prevent public health relevance response segregation vector-borne

项目摘要

Project Summary A central question in the study of cell cycle regulation is, how the cell cycle transitions are controlled to allow the transition to the next cell cycle stage at a right time? Such control mechanisms are critical for maintaining genome integrity because premature transition from one stage to the next stage of the cell cycle can lead to aneuploidy and, hence, cell death. Four major cell cycle transition points, the G1/S transition, the G2/M transition, the metaphase/anaphase transition, and the mitosis/cytokinesis transition, are under stringent control, but how they are regulated at the molecular level in T. brucei, a protozoan parasite and the causative agent of human sleeping sickness, remains poorly understood. Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle transitions in eukaryotes, and T. brucei employs the CDK-related kinase CRK1 to control the G1/S transition, CRK2 to promote S-phase progression, and CRK3 to govern the G2/M transition. The roles of CRK1 in controlling the nuclear events in promoting the G1/S transition and the role of CRK2 in regulating S-phase progression have been recently revealed by us. However, the molecular mechanisms underlying the G2/M transition and the metaphase/anaphase transition are still elusive. Further, it is generally accepted that T. brucei lacks several cell cycle checkpoints, including the spindle assembly checkpoint, and it is unclear how T. brucei recognizes the genomic errors occurred during the cell cycle and prevents erroneous genome duplication and premature genome segregation. Our recent discovery of a novel DNA damage- induced metaphase checkpoint suggests a kinetochore-based checkpoint machinery in T. brucei, but the underlying mechanism remains largely unknown. The current proposal aims to understand the control of the G2/M transition by CRK3-mediated regulation of the chromosomal passenger complex, the control of metaphase/anaphase transition by CRK3-mediated regulation of kinetochore proteins, and the mechanism of the metaphase checkpoint mediated by KKIP5 and its associated proteins. The outcomes from these investigations not only will have important biological significance, but also could provide novel targets for anti- trypanosomiasis chemotherapy.

项目概要细胞周期调控研究的一个中心问题是如何控制细胞周期转变允许在适当的时间过渡到下一个细胞周期阶段？这种控制机制对于保持基因组完整性，因为从细胞周期的一个阶段到下一阶段的过早转变可导致非整倍体，从而导致细胞死亡。四个主要的细胞周期转变点：G1/S 转变、 G2/M 转变、中期/后期转变和有丝分裂/细胞分裂转变受到严格限制控制，但它们如何在T. brucei（一种原生动物寄生虫及其致病原因）的分子水平上受到调节人类昏睡病的病原体，目前仍知之甚少。细胞周期蛋白依赖性激酶 (CDK) 是关键 T. brucei 是真核生物细胞周期转变的调节因子，T. brucei 利用 CDK 相关激酶 CRK1 CRK2 控制 G1/S 转变，CRK2 促进 S 期进展，CRK3 控制 G2/M 转变。 CRK1在控制核事件促进G1/S转变中的作用以及CRK2在促进G1/S转变中的作用我们最近揭示了调节 S 期进展的方法。然而，分子机制 G2/M 转变和中期/后期转变的基础仍然难以捉摸。此外，一般来说承认布氏锥虫缺乏几个细胞周期检查点，包括纺锤体组装检查点，并且它目前还不清楚布氏锥虫如何识别细胞周期中发生的基因组错误并防止错误发生基因组复制和过早的基因组分离。我们最近发现了一种新的 DNA 损伤—— 诱导的中期检查点表明 T. brucei 中存在基于动粒的检查点机制，但根本机制仍然很大程度上未知。当前的提案旨在了解对 G2/M 转变通过 CRK3 介导的染色体过客复合体调控， CRK3介导的着丝粒蛋白调节的中期/后期转变及其机制由 KKIP5 及其相关蛋白介导的中期检查点。这些结果研究不仅具有重要的生物学意义，而且可以为抗肿瘤药物提供新的靶点。锥虫病化疗。