Nuclear DNA Replication Initiation Machinery in Trypanosomes

锥虫中的核 DNA 复制起始机制

• 批准号: 8069344
• 负责人: Michele M Klingbeil
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-06 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069344
• 关键词: ATP phosphohydrolase; Address; Affinity; Affinity Chromatography; African Trypanosomiasis; Area; Binding; Biochemical; Biological; Biological Assay; Biology; Blood Circulation; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Line; Chagas Disease; Chromatin; Complex; DNA; DNA Binding; DNA biosynthesis; DNA replication origin; Disease; Drug Delivery Systems; Drug resistance; Eukaryota; Foundations; Gene Expression Regulation; Genetic; Genome; Genome Stability; Human; Immunoprecipitation; In Vitro; Intervention; Kinetoplast DNA; Left; Leishmaniasis; Life; Life Cycle Stages; Mass Spectrum Analysis; Metabolism; Mitochondria; Modeling; Nuclear; Organism; Parasites; Pathway interactions; Pharmaceutical Preparations; Process; Property; Proteins; Public Health; RNA Interference; Regulation; Replication Initiation; Replication Origin; Research; Role; Structure; System; Toxic effect; Trypanosoma; Trypanosoma brucei brucei; Vaccines; base; design; fascinate; frontier; high throughput technology; human DNA; human disease; in vivo; insight; mutant; novel; novel therapeutic intervention; origin recognition complex; pathogen; protein complex; protein protein interaction; public health relevance; research study; synthetic construct; tool

DESCRIPTION (provided by applicant): Trypanosomatid organisms cause devastating and life-threatening human disease. Several unique biological properties are being pursued as potential new drug targets for much needed chemotherapeutic interventions. While studies on the mitochondrial kinetoplast DNA network are quite advanced, little information is available about nuclear DNA replication mechanisms or the machinery involved in replication initiation, called Origin Recognition Complex (ORC). In contrast to the six-subunit (Orc1-6) Origin Recognition Complex (ORC) found in all other model eukaryotes, the Tritryp genomes predict just a single ORC subunit, Orc1. In this proposal we will investigate function of this core DNA replication initiation protein, identify other protein components that might participate in origin binding, and identify DNA replication origins. Completion of these specific aims will have a major impact on the field, as they will address a critical gap in our understanding of a basic essential process in Trypanosoma brucei, and lay the foundation for a new frontier in trypanosome biology. Functional characterization of T. brucei Orc1 and interacting proteins may allow use to exploit any differences between trypanosomatid and mammalian replication initiation mechanisms to develop new strategies for drug treatment. Studies on T. brucei Orc1 also offer an opportunity to uncover insights into alternative mechanisms of eukaryotic DNA replication that may be applicable to other parasite systems. PUBLIC HEALTH RELEVANCE: This research is highly relevant to public health because trypanosomatids cause serious and fatal disease around the world for which current therapies are woefully inadequate. DNA replication initiation is fundamental for parasite survival, and core components differ substantially from the host. The proposed studies will greatly advance our understanding of alternative mechanisms of eukaryotic DNA replication initiation, and is a promising approach to novel therapeutic intervention in trypanosomatid pathogens.

描述（由申请人提供）：锥虫生物会导致毁灭性和威胁生命的人类疾病。正在将几种独特的生物学特性作为急需的化学治疗干预措施的潜在新药物靶标。虽然对线粒体动力学DNA网络的研究非常先进，但几乎没有有关核DNA复制机制或参与复制启动的机制的信息，称为Origin识别复合物（ORC）。与在所有其他模型真核生物中发现的六亚基（ORC1-6）起源识别复合物（ORC）相反，TRITRYP基因组仅预测一个单一的ORC亚基ORC1。在此提案中，我们将研究该核心DNA复制起始蛋白的功能，鉴定可能参与原始结合的其他蛋白质成分，并确定DNA复制起源。这些特定目标的完成将对该领域产生重大影响，因为它们将解决我们对Brucei锥虫瘤基本基本过程的关键差距，并为锥虫生物学的新边界奠定了基础。 T. brucei orc1和相互作用蛋白的功能表征可以允许利用锥虫和哺乳动物复制起始机制之间的任何差异，以制定新的药物治疗策略。关于布鲁氏菌ORC1的研究还提供了一个机会，可以发现可能适用于其他寄生虫系统的真核DNA复制的替代机制。 公共卫生相关性：这项研究与公共卫生高度相关，因为锥虫剂引起了全球严重和致命疾病，而当前疗法严重不足。 DNA复制引发是寄生虫生存的基础，而核心成分与宿主有很大不同。拟议的研究将大大提高我们对真核DNA复制启动的替代机制的理解，并且是对锥虫病原体新型治疗干预的一种有前途的方法。