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.

项目总结/描述