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 聚合酶 theta（Pol q，基因名称 Polq）在许多遗传性乳腺癌中至关重要，但 Pol q 的缺失 在大多数正常细胞中具有良好的耐受性。因此，开发过程中出现了很多令人兴奋的事情 用于癌症治疗的 Pol q 靶向抑制剂。然而，我们对其生物学作用知之甚少， 这个大的、多领域因素的作用机制。因此不可能调和不同的、 Pol q 丢失对突变、染色体畸变和细胞存活的明显依赖于环境的影响， Pol q 的安全、有效的靶向治疗在很大程度上受到了阻碍。 在总体目标 1 中，全长 Pol q 和 Pol q 域有助于修复的机制将是 通过使用生化、结构、遗传和生物物理成像进行并行分析来表征 我们的计划可用的方法。完整的通路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 从这些其他目标中获得的成果旨在为癌症治疗中更安全、有效地靶向 Pol q 提供理论依据。 研究工作将在三个核心框架内高度协调。 设施。底物、蛋白质和实验将与所有项目一起设计，并持续监控 通过管理核心 A 反馈。蛋白质纯化将由核心 B 和细胞系构建支持 通过核心 C. 科学项目负责人拥有互补的专业知识：博士。 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）Sylvie Doublié （结构生物学和机制；项目 3）和 Eli Rothenberg（生物物理学；项目 4）。这个乐团的 互补的专业知识促进了对整个团队有益的想法的交叉传播，并使工作 这可能只能通过计划项目拨款来完成。这支队伍也已经有很长的路要走 富有成效的合作记录，并且在该计划内，项目将有效地协同工作，以 实现该计划的目标。该计划项目获得的结果将为 对支持 TMEJ 的分子机制的理解取得了进展，并将为 TMEJ 铺平道路 通过 Pol θ 抑制设计新型癌症疗法。