Polymerase theta, genome instability, and cancer

聚合酶θ、基因组不稳定性和癌症

• 批准号: 10468628
• 负责人: DALE A RAMSDEN
• 金额: $ 178.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468628
• 关键词: Acute; Address; Biochemical; Biochemistry; Biological; Biological Assay; Biophysics; Camptothecin; Candidate Disease Gene; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Assay; Cellular biology; Chromosome abnormality; Collaborations; Complex; Core Facility; Core Protein; DNA Damage; DNA Repair; DNA replication fork; DNA-Directed DNA Polymerase; Development; Double Strand Break Repair; Enzymes; Feedback; Fertilization; Fostering; Genes; Genetic; Genetic study; Genomic Instability; Genomics; Goals; Hereditary Breast Carcinoma; Human; Imaging Techniques; Knowledge; Length; Malignant Neoplasms; Measures; Mediating; Methods; Modeling; Molecular; Molecular Biology; Monitor; Mutation; Names; Nonhomologous DNA End Joining; Normal Cell; Pathway interactions; Polymerase; Program Research Project Grants; Proteins; Radiation; Reagent; Research; Role; Structural Models; Variant; Visualization; Wood material; Work; brca gene; cancer cell; cancer therapy; design; enzyme activity; established cell line; experimental study; homologous recombination; imaging approach; inhibitor; insight; mutant; novel; programs; protein purification; reconstitution; repaired; response; single molecule; small molecule; small molecule inhibitor; structural biology; vif Genes

PROJECT SUMMARY/DESCRIPTION Polymerase theta (Pol q, gene name Polq) is essential in many hereditary breast cancers, yet loss of Pol q is well tolerated in most normal cells. As a consequence, there has been much excitement in the development of targeted inhibitors of Pol q for cancer therapy. However, we know little about the biological role and mechanism of action for this large, multi-domain factor. It has thus not been possible to reconcile the disparate, apparently context-dependent impacts of Pol q loss on mutation, chromosome aberration, and cell survival, and the safe, effective targeting of Pol q for therapy has been largely frustrated. In overall Aim 1, the mechanism by which full-length Pol q and Pol q domains contribute to repair will be characterized by parallel analysis using the biochemical, structural, genetic and biophysical imaging approaches available to our program. Full pathway reconstitution and visualization is a goal. In Overall Aim 2 we will investigate the cellular contexts that normally engage Pol q. In Overall Aim 3 we will integrate insights gained from these other Aims to develop rationales for safer, effective targeting of Pol q in cancer therapy. The research work will be highly coordinated within the Program Project in a framework with three Core facilities. Substrates, proteins, and experiments will be designed with all Projects and constantly monitored with feedback via Administrative Core A. Protein purification will be supported by Core B, and cell line construction by Core C. The scientific project leaders have complementary expertise: Drs. Dale Ramsden (molecular biology; Project 1), Gaorav Gupta (cancer cell biology; Project 1), Richard Wood (biochemistry, Project 2) Sylvie Doublié (structural biology and mechanism; Project 3), and Eli Rothenberg (biophysics; Project 4). This ensemble of complementary expertise fosters cross-fertilization of ideas beneficial to the whole team, and makes work possible that can only be accomplished by a Program Project grant. This team also already has a long track record of productive collaboration, and within this program project will work effectively and synergistically to accomplish the Program’s goals. The results obtained by this Program Project will provide a fundamental advance in the understanding of the molecular mechanisms underpinning TMEJ, and will pave the way for the design of novel cancer therapy via Pol θ inhibition.

项目摘要/描述 在许多遗传性乳腺癌中，聚合酶theta（pol q，gene name polq）是必不可少的，但失去pol q是 在大多数正常细胞中耐受性良好。结果，发展有很多兴奋 POL Q的靶向抑制剂进行癌症治疗。但是，我们对生物学作用一无所知 这个大型多域因子的作用机理。因此，不可能调和不同的 显然，Pol Q丢失对突变，染色体像差和细胞存活的影响显然与上下文有关的影响， 在很大程度上，对治疗的安全有效靶向治疗。 在总体目标1中，全长Pol Q和Pol Q域有助于维修的机制是 使用生化，结构，遗传和生物物理成像的平行分析的特征 我们计划可用的方法。完整的路径重建和可视化是一个目标。总体目标2 我们将研究通常与POL Q相关的细胞环境。在总体目标3中，我们将整合见解 从这些其他目的中获得的，旨在发展癌症治疗中POL Q的更安全，有效的靶向。 该研究工作将在计划项目中高度协调，并具有三个核心 设施。底物，蛋白质和实验将通过所有项目设计，并不断监控 通过管理核心A的反馈A蛋白质净化将由核心B和细胞系构建支持 由CoreC。 科学项目领导者拥有完整的专业知识：Drs。戴尔·拉姆斯登（Dale Ramsden）（分子生物学；项目 1），Gaorav Gupta（癌细胞生物学；项目1），Richard Wood（生物化学，项目2）SylvieDoubleé （结构生物学和机制；项目3）和Eli Rothenberg（生物物理学；项目4）。这个合奏 完全专业的知识促进了对整个团队有益的想法的交叉施肥，并进行工作 只有计划项目赠款才能实现。该团队也已经有很长的路线 产品合作的记录，该计划项目中将有效，协同工作 实现计划的目标。该计划项目获得的结果将提供基本 在理解TMEJ支撑的分子机制方面发展，并将为 通过polθ抑制作用的新型癌症治疗设计。