BRCA-dependent Mechanisms of Genome Maintenance and Repair

摘要 DNA双链断裂是最有害的DNA损伤之一，如果不是 处理不当，会导致大的染色体异常，细胞的肿瘤性转化，以及 肿瘤发生学。NCI资助的单位主任Patrick Sung博士的研究计划专注于 关于阐明保守的同源重组(HR)机制，DSB通过这些机制被 得到了忠实的修复。通过包括生化重建在内的跨学科方法， 生物物理分析、结构生物学和基于细胞的研究，Sung实验室拥有 提供了对人力资源关键步骤的见解。现有的实验和智力框架 使我们能够继续描绘人力资源和DSB维修流程的机械复杂性， 为了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， 复制叉状细胞死亡、肿瘤细胞转化和癌症。 作为研究副教授，我一直在为阐明潜在的 HR的三个关键阶段，即RAD51突触前微丝组装、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。在本R50研究专家中 申请获奖，我要求工资支持，使我能够帮助推动有针对性的研究工作 在阐明肿瘤抑制基因BRCA1-BARD1、BRCA2、FANCJ、 其伴随的人力资源因素在人力资源流程的上述阶段和在DNA中实现 复制分叉保存。因此，R50研究专家奖不仅有助于推动 我们的研究目标，也将在DNA修复和癌症生物学方面产生更广泛的影响 随着我继续设计新的生化分析方法和用纯化的HR重组的系统 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 支点指向刺激小分子化合物作为化学生物学工具和 潜在的癌症疗法。[我将继续就以下所有事项向股长提供咨询意见 我们研究计划的总体方向，承担着指导和 培养博士生和博士后研究员，发挥校内沟通的主渠道作用 以及校外合作者。我将担任我所从事的研究的通讯作者 发挥领导作用，出席重要会议传播我的研究成果，以及 在我个人功劳的基础上建立起国家声誉。]

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. 】