BRCA-dependent Mechanisms of Genome Maintenance and Repair

BRCA 依赖的基因组维护和修复机制

• 批准号: 10516336
• 负责人: YOUNGHO KWON
• 金额: $ 16.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516336
• 关键词: Award; BARD1 gene; BRCA1 gene; BRCA2 gene; Biochemical; Biological Assay; Biology; Cancer Biology; Cells; Chemicals; Chromosome abnormality; Companions; DNA; DNA Double Strand Break; DNA Repair; DNA biosynthesis; DNA lesion; DNA replication fork; Development; Double Strand Break Repair; Extramural Activities; Filament; Funding; Gene Mutation; Genome; Genomic Instability; Growth; Health; Investigation; Laboratories; Lead; Leadership; Maintenance; Malignant Neoplasms; Mediating; Mentors; Neoplastic Cell Transformation; Pathway interactions; Play; Positioning Attribute; Postdoctoral Fellow; Process; Productivity; Research; Role; Specialist; System; Texas; Therapeutic; Training; Tumor Suppressor Proteins; Universities; Wages; base; biophysical analysis; career; doctoral student; graduate student; homologous recombination; insight; mid-career faculty; novel; preservation; presynaptic; programs; reconstitution; repaired; small molecule; structural biology; symposium; tool; tumorigenesis

ABSTRACT DNA double-strand breaks (DSBs) are among the most deleterious of DNA lesions and, if not handled properly, can lead to gross chromosome aberrations, neoplastic transformation of cells, and tumorigenesis. The NCI-funded research program of the Unit Director Dr. Patrick Sung has focused on elucidating conserved homologous recombination (HR) mechanisms, by which DSBs are being faithfully repaired. Through a transdisciplinary approach encompassing biochemical reconstitution, biophysical analysis, structural biology, and cell-based investigations, the Sung laboratory has provided insights into critical steps of HR. The available experimental and intellectual framework ideally positions us to continue delineating the mechanistic intricacy of HR and DSB repair processes, to provide actionable information for explaining why HR gene mutations lead to genome instability, replication fork demise, neoplastic cell transformation, and cancer. As Research Associate Professor, I have been making contributions in elucidating the underlying mechanisms of three critical stages of HR, namely, RAD51 presynaptic filament assembly, DNA strand invasion, and repair DNA synthesis. I have also played a key role in the training and mentoring of graduate students and research fellows in the Sung laboratory. In this R50 Research Specialist Award application, I request salary support to enable me to help drive research endeavors directed at elucidating the multifaceted roles that the tumor suppressors BRCA1-BARD1, BRCA2, FANCJ, and their companion HR factors fulfill in the aforementioned stages of the HR process and in DNA replication fork preservation. As such, the R50 Research Specialist Award will not only help advance our research objectives, but will also exert a broader impact in the DNA repair and cancer biology fields as I continue to devise novel biochemical assays and systems reconstituted with purified HR factors to facilitate the studies of other laboratories, and will help identify novel targets and pathway pivot points to spur the development of small molecule compounds as chemical biology tools and potential cancer therapeutics. 【 I will continue to advise the Unit Director in all matters concerning the general directions of our research program, take on major responsibilities in mentoring and training of doctoral students and postdoctoral fellows, and act as the main conduit with intramural and extramural collaborators. I will serve as the corresponding author on studies in which I have played a leadership role, attend major conferences to disseminate my research findings, and develop a national reputation based on my own merit. 】

摘要 DNA双链断裂（DSB）是最有害的DNA损伤之一， 处理不当，可导致染色体畸变，细胞的肿瘤转化， 肿瘤发生该研究所所长帕特里克宋博士的国家癌症研究所资助的研究计划， 阐明了保守的同源重组（HR）机制，通过这种机制， 忠实修复通过跨学科的方法，包括生化重建， 生物物理分析，结构生物学和基于细胞的研究，Sung实验室 提供了对人力资源的关键步骤的见解。现有的实验和知识框架 理想地使我们能够继续描绘HR和DSB修复过程的机械复杂性， 为解释为什么HR基因突变导致基因组不稳定性提供可操作的信息， 复制叉死亡、肿瘤细胞转化和癌症。 作为研究副教授，我一直致力于阐明 HR的三个关键阶段，即RAD51突触前纤维组装，DNA 链侵入和修复DNA合成。我还在培训和指导方面发挥了关键作用， 的研究生和研究员在宋实验室。在这个R50研究专家 奖项申请，我要求工资支持，使我能够帮助推动研究工作的方向 在阐明肿瘤抑制因子BRCA 1-BARD 1，BRCA 2，FANCJ， 以及它们的伴随HR因子在HR过程的上述阶段和DNA中实现 复制叉保存。因此，R50研究专家奖不仅有助于推动 我们的研究目标，但也将发挥更广泛的影响，在DNA修复和癌症生物学 随着我继续设计新的生化测定和用纯化的HR重建的系统， 这些因素有助于其他实验室的研究，并将有助于确定新的靶点和途径 促进小分子化合物作为化学生物学工具的发展的支点， 潜在的癌症治疗方法。[我将继续就有关下列事项向股长提供咨询意见： 我们的研究计划的总体方向，承担指导的主要责任， 培养博士生和博士后研究员，并作为主要渠道与校内 和校外合作者我将作为通讯作者的研究，我有 发挥了领导作用，参加主要会议，传播我的研究成果， 以我自己的功绩建立起国家声誉】