Structural Cell Biology of DNA Repair Machines
DNA 修复机的结构细胞生物学
基本信息
- 批准号:8153344
- 负责人:
- 金额:$ 298.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-27 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisAreaBiochemicalBiochemistryBiocompatible MaterialsBiologicalBiological AssayBiological ProcessCancer EtiologyCancer InterventionCell AgingCell Cycle CheckpointCell divisionCell physiologyCellsCellular biologyChemicalsComplexCouplingCultured CellsDNADNA DamageDNA MaintenanceDNA RepairDNA Repair PathwayDNA Single Strand BreakDNA repair proteinDefectDetectionDevelopmentDevelopmental Therapeutics ProgramDiseaseEnzymesExcisionGeneric DrugsGenetic RecombinationGenetic TranscriptionGenomic InstabilityGoalsIn VitroIndividualIndividual DifferencesInterventionInvestmentsKnowledgeLaboratoriesLeadLigationMalignant NeoplasmsMethodsModelingMolecular BiologyMolecular ConformationMutationNormal CellNucleotide Excision RepairOncogenicOutcomePathway interactionsPhysiologicalPost-Translational Protein ProcessingPredispositionProcessProteinsRadiationRecurrenceRepair ComplexResearch PersonnelResistanceResolutionRoentgen RaysScreening procedureSignal TransductionSolutionsStructureTestingTherapeuticTranslatingTreatment FailureUnited States National Institutes of HealthValidationWorkX-Ray Crystallographybasecancer cellcancer initiationcancer recurrencecancer therapycarcinogenesischemotherapydesigneffective interventionflexibilityimprovedinhibitor/antagonistkillingsneoplastic cellprogramsprotein protein interactionrepairedresearch studyresponsesmall moleculestructural biologytumortumor initiation
项目摘要
DESCRIPTION (provided by applicant): We are studying the structural organization of DNA repair complexes that excise DNA damage and the functional consequences of disrupting these protein-protein interactions by mutation and small molecule inhibitors. Alternative pathways of repair are available for many types of DNA damage, and posttranslational modifications generated in response to DNA damage control the differential assembly of repair complexes, providing a mechanism for regulating pathway choice. Cancer-associated defects in DNA maintenance activities can be exploited therapeutically by targeting the remaining repair activities with mechanism-based inhibitors. Our work focuses on the mechanisms of repairing DNA single strand breaks generated by the base excision and nucleotide excision repair pathways. We are studying the physical assembly of DNA damage excision complexes in vitro and in cultured cells, and the mechanism of coupling DNA cleavage to end processing and ligation. Small angle x-ray scattering of purified DNA repair complexes reveals dynamic conformational states that we propose are important for handoffs of DNA repair intermediates to successive enzymes in a pathway. High resolution crystal structures and small molecule screening experiments are being used to predict and identify inhibitors of repair protein interactions, which are candidates for anti-tumor therapies and serve as reversible chemical probes of cellular physiology during DNA damage responses. This integrated approach takes advantage of the broad expertise of investigators in Projects 1, 2, and 6 for assays and biological materials, as well as the unique capabilities of the Expression and Molecular Biology Core and the Structural Cell Biology Core of the SBDR Program to produce proteins and structurally evaluate repair complexes.
描述(由申请人提供):我们正在研究DNA修复复合物的结构组织,该复合物切除DNA损伤以及通过突变和小分子抑制剂破坏这些蛋白质-蛋白质相互作用的功能后果。修复的替代途径可用于许多类型的DNA损伤,并且响应于DNA损伤产生的翻译后修饰控制修复复合物的差异组装,提供调节途径选择的机制。癌症相关的DNA维持活动的缺陷可以通过靶向剩余的修复活动与机制为基础的抑制剂在治疗上利用。我们的工作主要集中在碱基切除修复途径和核苷酸切除修复途径修复DNA单链断裂的机制。我们正在研究DNA损伤切除复合物在体外和培养细胞中的物理组装,以及DNA切割与末端加工和连接的耦合机制。纯化的DNA修复复合物的小角X-射线散射揭示了动态构象状态,我们建议是重要的DNA修复中间体,连续酶的通路中的baffs。高分辨率晶体结构和小分子筛选实验正被用于预测和鉴定修复蛋白相互作用的抑制剂,其是抗肿瘤疗法的候选者,并在DNA损伤反应期间充当细胞生理学的可逆化学探针。 这种综合方法利用了项目1、2和6中研究人员在测定和生物材料方面的广泛专业知识,以及SBDR计划的表达和分子生物学核心和结构细胞生物学核心的独特能力,以生产蛋白质和结构评估修复复合物。
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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John A. Tainer其他文献
Molecular model of TFIIH recruitment to the transcription-coupled repair machinery
TFIIH 招募到转录偶联修复机制的分子模型
- DOI:
10.1038/s41467-025-57593-0 - 发表时间:
2025-03-08 - 期刊:
- 影响因子:15.700
- 作者:
Tanmoy Paul;Chunli Yan;Jina Yu;Susan E. Tsutakawa;John A. Tainer;Dong Wang;Ivaylo Ivanov - 通讯作者:
Ivaylo Ivanov
DNA repair without flipping out
DNA 修复而不抓狂
- DOI:
10.1038/nature15646 - 发表时间:
2015-10-28 - 期刊:
- 影响因子:48.500
- 作者:
David S. Shin;John A. Tainer - 通讯作者:
John A. Tainer
A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance
乳腺癌治疗耐药中表观遗传-代谢调节轴的棱柱形视图
- DOI:
10.1038/s41388-024-03054-9 - 发表时间:
2024-05-08 - 期刊:
- 影响因子:7.300
- 作者:
Chandrima Das;Apoorva Bhattacharya;Swagata Adhikari;Atanu Mondal;Payel Mondal;Santanu Adhikary;Siddhartha Roy;Kenneth Ramos;Kamlesh K. Yadav;John A. Tainer;Tej K. Pandita - 通讯作者:
Tej K. Pandita
Proteines de fusion ciblees par clycosaminoglycane, leurs conception, construction et compositions
糖胺聚糖融合蛋白、概念、结构和成分
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:0
- 作者:
John A. Tainer;Leslie A. Kuhn;Maurice Boissinot;Cindy L. Fisher;Hans E. Parge;J. H. Griffin;Guy Mullenbach;Robert A. Hallewell - 通讯作者:
Robert A. Hallewell
Multiscale Modeling of PCNA - Ubiquitin Interactions
- DOI:
10.1016/j.bpj.2009.12.2087 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Ivaylo Ivanov;Adam Van Wynsberghe;John A. Tainer;J. Andrew McCammon - 通讯作者:
J. Andrew McCammon
John A. Tainer的其他文献
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{{ truncateString('John A. Tainer', 18)}}的其他基金
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10687040 - 财政年份:2018
- 资助金额:
$ 298.1万 - 项目类别:
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10251045 - 财政年份:2018
- 资助金额:
$ 298.1万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8840824 - 财政年份:2012
- 资助金额:
$ 298.1万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8656719 - 财政年份:2012
- 资助金额:
$ 298.1万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8469234 - 财政年份:2012
- 资助金额:
$ 298.1万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8475491 - 财政年份:2012
- 资助金额:
$ 298.1万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
8212285 - 财政年份:2006
- 资助金额:
$ 298.1万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7767763 - 财政年份:2006
- 资助金额:
$ 298.1万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7096103 - 财政年份:2006
- 资助金额:
$ 298.1万 - 项目类别:
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