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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要同源重组（HR）是主要的染色体损伤修复工具。通过消除DNA双重链断裂和其他有害病变，HR对于维持基因组稳定性是必不可少的。在人类中，人力资源缺陷直接导致癌症。这个更新项目的重点是肿瘤的角色 HR介导的染色体修复中的抑制剂BRCA1，BARD1，BRCA2和PALB2。在最后一个资金期间取得了很大进展，导致了重要的进步了解人力资源机制。利用我们的成功，各种体外和体内研究将是进行HR中的BRCA1-BARD1-BRCA2-PALB2合奏的多方面角色由重组酶rad51催化的反应。关于人力资源因素如何的新颖假设促进人力资源反应的突触前阶段以及癌症突变如何影响此关键人力资源步骤进行测试。该更新项目的结果将继续提供有关功能的见解关键的人力资源因素，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肿瘤网络维护。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靶向人力资源途径的潜力治疗策略。此外，在我们的研究过程中生成的研究材料代表了DNA修复和癌症生物学研究社区的宝贵资源。