Eukaryotic Topoisomerase I
真核拓扑异构酶 I
基本信息
- 批准号:7578977
- 负责人:
- 金额:$ 31.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-05-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAftercareAntineoplastic AgentsBindingBiological AssayCamptothecinCellsChromosome DeletionComplexDNADNA BindingDNA DamageDNA LigasesDNA RepairDevelopmentEnzymesEquilibriumEukaryotic DNA Topoisomerase IExposure toGenetic RecombinationGoalsHumanKineticsLeishmania donovaniLeishmaniasisLesionLigationMediatingModelingModificationMolecularNaturePathway interactionsPeptidesPharmaceutical PreparationsPharmacotherapyPhosphoric Monoester HydrolasesPolynucleotide 5&apos-Hydroxyl-KinaseProceduresProcessPropertyProteinsReactionRepair ComplexResearchRoleSeriesSignal TransductionSolutionsSpecificityStructureSurfaceTestingTopoisomeraseType I DNA Topoisomerasesadductcell injuryds-DNAendonucleasehuman DNAhuman TOP1 proteinhuman XRCC1 proteiniliumin vivoinsightphosphoric diester hydrolaserepair enzymerepairedtyrosyl-DNA phosphodiesterase
项目摘要
DESCRIPTION (provided by applicant): The overall goals of the proposed research are to understand from a mechanistic and structure-function perspective how human topoisomerase I manages the topology of DNA in vivo, and how cells repair the damage that occurs when topoisomerase I becomes stalled in covalent complexes on the DNA. Such complexes result from topoisomerase I cleavage in the vicinity of several types of DNA damage and after treatment with the anticancer drug, camptothecin. A consideration of possible repair pathways will include both a detailed analysis of the properties of the enzyme, tyrosyl-DNA phosphodiesterase (Tdp1), and a test of an endonuclease-mediated repair hypothesis. The proposed studies will determine how the linker domain of topoisomerase I regulates the cleavage-religation equilibrium and whether this effect requires a direct interaction between the linker and the substrate DNA. A possible role for the linker in aligning the DNA for blunt-end ligation during illegitimate recombination leading to chromosomal deletions will be investigated. To gain insights into the nature of the in vivo substrates for Tdp1, a series of model structures with modifications in both the DNA and peptide moieties of the substrate will be tested in binding and cleavage assays. A procedure has been developed for the isolation of the topoisomerase I-DNA covalent complexes generated in vivo after exposing cells to camptothecin or expressing a "toxic" topoisomerase I. This procedure will be used to identify repair pathway intermediates that accumulate under conditions of limiting Tdp1. Preliminary results suggesting the possible involvement of an endonuclease in the repair of covalent complexes will also be pursued. To better understand how Tdp1 repairs topoisomerase l-related DNA damage and to investigate the likely possibility that Tdp1 also repairs other types of DNA damage, we will identify and characterize proteins that interact with Tdp1. These studies are medically important because topoisomerase I is the target of a variety of anticancer drugs and because elucidating how Tdp1 or other enzymes repair topoisomerase I-DNA covalent complexes may promote the development of new drugs that could be used in combination anticancer drug therapies. Finally, characterizing the accessory domains of the heterodimeric Leishmania donovani topoisomerase I will likely facilitate the development of new drugs that selectively target this atypical type IB topoisomerase for the treatment of Leishmaniasis.
描述(申请人提供):拟议研究的总体目标是从机制和结构-功能的角度了解人类拓扑异构酶I如何在体内管理DNA的拓扑结构,以及当拓扑异构酶I在DNA上的共价复合体中停滞时,细胞如何修复发生的损伤。这种复合体是在几种类型的DNA损伤附近发生拓扑异构酶I裂解,并在抗癌药物喜树碱治疗后产生的。对可能的修复途径的考虑将包括对酪氨酸二酯酶(Tdp1)的特性的详细分析,以及对核酸内切酶介导的修复假说的测试。拟议的研究将确定拓扑异构酶I的连接器域如何调节切割-宗教平衡,以及这种影响是否需要连接体和底物DNA之间的直接相互作用。在导致染色体缺失的非法重组过程中,连接子在对准DNA以进行钝端连接方面的可能作用将被调查。为了深入了解Tdp1体内底物的性质,将在结合和切割分析中测试一系列在底物的DNA和多肽部分都有修饰的模型结构。建立了一种分离拓扑异构酶I-DNA共价复合体的方法,该复合体是在细胞暴露于喜树碱或表达“毒性”拓扑异构酶I后在体内产生的,该程序将用于鉴定在限制Tdp1的条件下积累的修复途径中间产物。初步结果表明,核酸内切酶可能参与了共价复合体的修复。为了更好地了解Tdp1如何修复L拓扑异构酶相关的DNA损伤,并研究Tdp1也修复其他类型的dna损伤的可能性,我们将鉴定和鉴定与Tdp1相互作用的蛋白质。这些研究具有重要的医学意义,因为拓扑异构酶I是多种抗癌药物的靶点,而且阐明Tdp1或其他酶如何修复拓扑异构酶I-DNA共价复合体可能会促进可用于联合抗癌药物治疗的新药的开发。最后,表征异二聚体杜氏利什曼原虫拓扑异构酶I的辅助结构域可能会促进选择性靶向这种非典型类型IB拓扑异构酶治疗利什曼病的新药的开发。
项目成果
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JAMES J CHAMPOUX其他文献
JAMES J CHAMPOUX的其他文献
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{{ truncateString('JAMES J CHAMPOUX', 18)}}的其他基金
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