Genome Maintenance via the BRCA-PALB2 Tumor Suppressor Network

通过 BRCA-PALB2 肿瘤抑制网络进行基因组维护

• 批准号: 9752265
• 负责人: Patrick Sung
• 金额: $ 36.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752265
• 关键词: Affect; BARD1 gene; BRCA1 gene; BRCA2 gene; Biochemical; Biochemical Genetics; Biological; Biophysics; Breast; C-terminal; Cancer Biology; Cells; Chemical Agents; Chemicals; Chromosomes; Communities; Complex; Conflict (Psychology); DNA; DNA Binding; DNA Binding Domain; DNA Double Strand Break; DNA Repair; DNA lesion; DNA replication fork; Defect; Development; Ensure; Excision; Failure; Fanconi' s Anemia; Filament; Funding; Genes; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Human; In Vitro; Ionizing radiation; Lead; Lesion; Ligands; Light; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mutation; Ovarian; Pancreas; Pathway interactions; Phase; Primary Lesion; Proteins; Rad51 recombinase; Radiobiology; Reaction; Regimen; Research; Resources; Role; Single-Stranded DNA; Syndrome; Testing; Time; Tumor Suppression; Tumor Suppressor Proteins; base; chemotherapy; crosslink; genome integrity; homologous recombination; in vivo; insight; novel; nuclease; presynaptic; recombinase; recombinational repair; repaired; single molecule; success; targeted treatment; tool

PROJECT SUMMARY Homologous recombination (HR) is a major chromosome damage repair tool. By eliminating DNA double- strand breaks and other deleterious lesions, HR is indispensable for the maintenance of genome stability. In humans, defects in HR directly lead to cancer. This renewal project focuses on the roles of the tumor suppressors BRCA1, BARD1, BRCA2, and PALB2 in the HR-mediated repair of damaged chromosomes. Considerable progress has been made during the last funding period, leading to important advances in understanding HR mechanism. Capitalizing on our success, a variety of in vitro and in vivo studies will be conducted to delineate the multifaceted roles of the BRCA1-BARD1-BRCA2-PALB2 ensemble in the HR reaction that is catalyzed by the recombinase RAD51. Novel hypotheses regarding how the HR factors facilitate the presynaptic stage of the HR reaction and how cancer mutations affect this critical HR step will be tested. The results from this renewal project will continue to provide insights regarding the functions of key HR factors, and will allow us to formulate detailed models of chromosome damage repair and genome maintenance via the BRCA-PALB2 tumor suppressor network. Our studies have direct relevance to cancer biology and to the development of chemical compounds to evaluate the potential of HR pathway-targeted therapeutic strategies. Moreover, the research materials generated during the course of our studies represent an invaluable resource for the DNA repair and cancer biology research communities.

项目概要 同源重组（HR）是一种主要的染色体损伤修复工具。通过消除 DNA 双 链断裂和其他有害损伤，HR对于维持基因组稳定性是不可或缺的。 在人类中，心率缺陷直接导致癌症。该更新项目重点关注肿瘤的作用 HR 介导的受损染色体修复中的抑制因子 BRCA1、BARD1、BRCA2 和 PALB2。 在上一个资助期间取得了相当大的进展，在以下方面取得了重要进展： 了解人力资源机制。利用我们的成功，将进行各种体外和体内研究 旨在描述 BRCA1-BARD1-BRCA2-PALB2 整体在 HR 中的多方面作用 由重组酶 RAD51 催化的反应。关于人力资源因素如何影响的新假设 促进 HR 反应的突触前阶段以及癌症突变如何影响这一关键的 HR 步骤将 被测试。该更新项目的结果将继续提供有关以下功能的见解： 关键的 HR 因素，将使我们能够制定染色体损伤修复和基因组的详细模型 通过 BRCA-PALB2 肿瘤抑制网络进行维持。我们的研究与癌症直接相关 生物学和化学化合物的开发，以评估 HR 通路靶向的潜力 治疗策略。此外，我们在学习过程中产生的研究材料 代表了 DNA 修复和癌症生物学研究界的宝贵资源。