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. 】

抽象的 DNA 双链断裂 (DSB) 是最有害的 DNA 损伤之一，如果不是的话 如果处理不当，可能会导致严重的染色体畸变、细胞的肿瘤性转化，以及 肿瘤发生。单位主任 Patrick Sung 博士的 NCI 资助研究项目重点关注 阐明保守同源重组 (HR) 机制，通过该机制 DSB 被 忠实修复。通过包括生化重建在内的跨学科方法， Sung 实验室在生物物理分析、结构生物学和基于细胞的研究方面拥有 提供了对人力资源关键步骤的见解。可用的实验和知识框架 使我们能够继续描绘 HR 和 DSB 修复过程的机械复杂性， 提供可操作的信息来解释为什么 HR 基因突变导致基因组不稳定， 复制叉死亡、肿瘤细胞转化和癌症。 作为研究副教授，我一直在阐明基本原理方面做出了贡献 HR 三个关键阶段的机制，即 RAD51 突触前丝组装、DNA 链入侵，修复DNA合成。我还在培训和指导中发挥了关键作用 宋实验室的研究生和研究员。在这个 R50 研究专家中 奖项申请，我请求薪资支持，以便我能够帮助推动定向研究工作 阐明肿瘤抑制因子 BRCA1-BARD1、BRCA2、FANCJ、 及其伴随的人力资源因素在人力资源流程的上述阶段和 DNA 中实现 复制叉保存。因此，R50 研究专家奖不仅有助于推进 我们的研究目标，但也将对 DNA 修复和癌症生物学产生更广泛的影响 我继续设计新的生化检测方法和用纯化 HR 重建的系统 促进其他实验室研究的因素，并将有助于确定新的目标和途径 刺激小分子化合物作为化学生物学工具的发展的关键点 潜在的癌症治疗方法。 【 我将继续就有关的所有事宜向单位主任提供建议 我们研究计划的总体方向，承担指导和指导的主要责任 培养博士生和博士后，并作为校内交流的主要渠道 和校外合作者。我将担任我所从事的研究的通讯作者 发挥领导作用，参加主要会议来传播我的研究成果，以及 以我自己的功绩建立全国声誉。 】