Mechanisms of mitochondrial DNA replication licensing in trypanosomes
锥虫中线粒体 DNA 复制许可机制
基本信息
- 批准号:8300425
- 负责人:
- 金额:$ 22.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:26S proteasomeAdoptedAffinity ChromatographyAfricanAfrican TrypanosomiasisAnimalsBindingBiological AssayCatalytic DomainCell CycleCellsComplexCountryDNADNA biosynthesisDNA copy numberDiseaseDissectionDrug Delivery SystemsEnsureEukaryotaEukaryotic CellGene SilencingGenomeGenome StabilityGoalsGuide RNAHomologous GeneHumanInfectionKinetoplast DNALeishmaniaLicensingLicensing FactorMCM2 geneMaintenanceMediatingMessenger RNAMitochondriaMitochondrial DNAMitochondrial ProteinsMolecularMonitorMorphologyNamesNuclearParasite ControlParasitesParasitic DiseasesPeptide HydrolasesPharmaceutical PreparationsPhasePhysiologicalProteinsRNA InterferenceRecruitment ActivityRegulationRegulatory PathwayReplication LicensingReplication OriginRibosomal RNARiskRoleS PhaseSchemeShapesStructureSystemTestingTranscriptTrypanosomaTrypanosoma brucei bruceiTrypanosomiasisWorld Health Organizationchemotherapydrug developmentgenetic regulatory proteinhelicasein vivonovelnuclear divisionpreventreceptorresearch studysegregationvector
项目摘要
DESCRIPTION (provided by applicant): Maintenance of genomic stability requires accurate DNA replication. Eukaryotic cells achieve this by licensing the replication origins through recruiting the licensing factors to the origins to initiate replication and subsequently by 26S proteasome-mediated degradation of the licensing actors to prevent DNA re-replication. Eukaryotes must also maintain multiple copies of an extranuclear genome, the mitochondrial DNA (mtDNA), but the underlying mechanism for maintenance of mtDNA copy number remains a mystery. The current proposal is aimed at understanding the molecular mechanism of mtDNA replication licensing and is built on our recent discovery of HslVU protease as an essential regulator of mtDNA replication in Trypanosoma brucei, a protozoan parasite that contains an unusual mtDNA network, known as the kinetoplast DNA (kDNA). This protease is the first known regulator of kDNA replication and first bacterial-like HslVU protease identified in a eukaryote, but how it exerts its function is poorly understood, mainly because its regulatory proteins are not identified. Through tandem affinity purification, we identified two novel mitochondrial proteins that associate with TbHslVU in vivo, and we propose in this application to examine their potential roles in regulating TbHslVU as well as their potential involvement in kDNA replication. We hypothesize that the two novel proteins, named VUP1 and VUP2 for TbHslVU Partner 1 and 2, function as regulators of TbHslVU. They could either activate or inhibit the activity of TbHslVU or regulate the assembly of TbHslVU complex or mediate substrate recognition. The identification of regulatory proteins of TbHslVU suggests an additional level of control over the replication of kDNA and the complexity of the regulatory scheme of kDNA replication in trypanosomes. Most importantly, since no homologs of TbHslVU and its partners, VUP1 and VUP2, are found in humans, they are potential drug targets for anti-trypanosomiasis chemotherapy.
PUBLIC HEALTH RELEVANCE: Human African Trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. Current World Health Organization (WHO) estimates that around sixty million people in thirty-six sub-Saharan African countries are at risk of infection and 300,000 to 500,000 people are infected each year. Since drugs to cure the disease are few and often toxic to humans, further understanding of the parasite and drug development are urgently needed. Trypanosomes possess a unique mitochondrial DNA complex, kinetoplast DNA (kDNA), whose replication is under tight control and is essential for trypanosome survival. The proposed studies in this application will explore the mechanism of kDNA replication licensing by identifying and characterizing two novel proteins, VUP1 and VUP2, both of which are regulators of a novel mitochondrial protease, TbHslVU. TbHslVU is a structural equivalent of the eukaryotic 26S proteasome complex and does not have a homolog in humans. Therefore TbHslVU and its regulatory proteins are potential drug targets for anti-trypanosomiasis chemotherapy.
描述(由申请人提供):基因组稳定性的维持需要准确的DNA复制。真核细胞通过将许可因子募集到复制起点以启动复制,随后通过26S蛋白酶体介导的许可因子降解以防止DNA再复制,从而许可复制起点来实现这一点。真核生物也必须维持一个多核基因组的多个拷贝,即线粒体DNA(mtDNA),但维持mtDNA拷贝数的潜在机制仍然是一个谜。目前的建议是旨在了解mtDNA复制许可的分子机制,并建立在我们最近发现的HslVU蛋白酶作为一个重要的调节剂的mtDNA复制在布氏锥虫,一种原生动物寄生虫,包含一个不寻常的mtDNA网络,称为动基体DNA(kDNA)。这种蛋白酶是第一个已知的kDNA复制调节因子,也是第一个在真核生物中发现的类细菌HslVU蛋白酶,但人们对其如何发挥其功能知之甚少,主要是因为其调节蛋白尚未被鉴定。通过串联亲和纯化,我们鉴定了两种在体内与TbHslVU相关的新型线粒体蛋白,并且我们在本申请中提出检查它们在调节TbHslVU中的潜在作用以及它们在kDNA复制中的潜在参与。我们假设两种新的蛋白质,命名为VUP1和VUP2的TbHslVU伴侣1和2,作为调节剂的TbHslVU的功能。它们可以激活或抑制TbHslVU的活性,或调节TbHslVU复合物的组装,或介导底物识别。TbHslVU的调节蛋白的鉴定表明对kDNA复制的额外水平的控制和锥虫中kDNA复制的调节方案的复杂性。最重要的是,由于在人类中没有发现TbHslVU及其配偶体VUP1和VUP2的同源物,因此它们是抗锥虫化疗的潜在药物靶标。
公共卫生相关性:人类非洲锥虫病,也称为昏睡病,是一种媒介传播的寄生虫病。目前世界卫生组织(WHO)估计,在36个撒哈拉以南非洲国家,约有6000万人面临感染风险,每年有30万至50万人感染。由于治疗这种疾病的药物很少,而且通常对人类有毒,因此迫切需要进一步了解寄生虫和药物开发。锥虫具有独特的线粒体DNA复合物,动基体DNA(kDNA),其复制受到严格控制,并且是锥虫生存所必需的。本申请中提出的研究将通过鉴定和表征两种新型蛋白质VUP1和VUP2来探索kDNA复制许可的机制,这两种蛋白质都是新型线粒体蛋白酶TbHslVU的调节剂。TbHslVU是真核26S蛋白酶体复合物的结构等同物,并且在人类中不具有同源物。因此,TbHslVU及其调节蛋白是抗锥虫化疗的潜在药物靶标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ziyin Li其他文献
Ziyin Li的其他文献
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{{ truncateString('Ziyin Li', 18)}}的其他基金
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
- 批准号:
10619553 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
Regulation of cell cycle transition by a 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
- 批准号:
9896765 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
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
- 批准号:
10362149 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
Regulation of cell cycle transition by a 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
- 批准号:
9177113 - 财政年份:2016
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms of the Unusual Cytokinesis in Trypanosomes
锥虫异常细胞分裂的机制
- 批准号:
8505659 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms Of The Unusual Cytokinesis In Trypanosomes
锥虫异常细胞分裂的机制
- 批准号:
10440902 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms Of The Unusual Cytokinesis In Trypanosomes
锥虫异常细胞分裂的机制
- 批准号:
10581682 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms of the unusual cytokinesis in trypanosomes
锥虫异常胞质分裂的机制
- 批准号:
10179302 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms of the Unusual Cytokinesis in Trypanosomes
锥虫异常细胞分裂的机制
- 批准号:
8672593 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
Mechanisms of the unusual cytokinesis in trypanosomes
锥虫异常胞质分裂的机制
- 批准号:
9310309 - 财政年份:2013
- 资助金额:
$ 22.8万 - 项目类别:
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