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（由申请方提供）：锥虫微生物引起毁灭性和危及生命的人类疾病。一些独特的生物学特性正在被追求作为急需的化疗干预的潜在的新的药物靶点。虽然对线粒体动质体DNA网络的研究相当先进，但关于核DNA复制机制或复制起始所涉及的机制（称为起源识别复合物（ORC））的信息很少。与所有其他模式真核生物中发现的六亚基（Orc 1 -6）起源识别复合物（ORC）相反，Tritryp基因组预测只有一个单一的ORC亚基Orc 1。在这个建议中，我们将调查这个核心DNA复制起始蛋白的功能，确定其他蛋白质成分，可能参与原点结合，并确定DNA复制起点。这些具体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布氏锥虫基本过程的理解中的关键差距，并为锥虫生物学的新前沿奠定基础。T.布氏锥虫Orc 1和相互作用蛋白质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来开发用于药物治疗的新策略。对T.布氏菌Orc 1也提供了一个机会，以揭示真核DNA复制的替代机制，可能适用于其他寄生虫系统的见解。 公共卫生相关性：这项研究与公共卫生高度相关，因为锥虫在世界各地引起严重和致命的疾病，目前的治疗方法严重不足。DNA复制起始是寄生虫生存的基础，核心成分与宿主有很大不同。拟议的研究将大大推进我们对真核DNA复制启动的替代机制的理解，并且是一种有前途的方法，以新的治疗锥虫病原体的干预。