Understanding and Targeting the DNA Repair Network in Cancer

了解和靶向癌症中的DNA修复网络 描述：基因组不稳定是癌细胞的一个特征。同源 重组(HR)介导的DNA修复代表了一种无错误的修复机制 保持基因组的完整性，确保遗传信息的高保真传输。我的 长期目标是建立一个成功和可持续的独立研究计划 在利用基因组和蛋白质组研究HR修复方面具有核心竞争力 接近了。在我独立的职业生涯中，我希望攻读(1)基础研究 了解HR介导的DNA修复及其在肿瘤发生中的功能障碍和(2) 基于机制的翻译研究翻译人力资源的根本性突破 修复在癌症预防、诊断、预后和治疗中的临床应用 心理治疗。 我提议的研究的总体目标，这将为我的 独立的研究生涯，是为了了解人类Ago2的新的核功能， RNA干扰途径中的核心蛋白，在HR修复和基因组维护中起作用。 根据我的初步数据，我假设在DNA损伤反应的背景下， 通过翻译后修饰微调的调控机制，潜在地 通过ATM/ATR依赖的磷酸化，人核Ago2调节心率 通过在损伤部位招募DNA修复蛋白修复双链断裂 蛋白质之间的相互作用。我将通过以下三个具体目标来检验这一假设 机构与功能研究相结合的综合平台：(1)确定 Ago2作为一种新的调节因子在心率修复中的作用。(2)描述翻译后的特征 DNA损伤诱导的Ago2在HR修复中的修饰(3)确定核子 Ago2在防止基因组不稳定性和肿瘤发生中的作用。建议数 研究之所以重要，是因为它挑战了人类目前的研究范式 AGO2主要在细胞质中发挥作用。这项研究将阐明2 进化上保守的基因组防御机制，小调节RNA 通路和DNA损伤反应通路，在DNA损伤过程中汇聚 通过Ago2蛋白的功能参与，促进HR的修复。

UNDERSTANDING AND TARGETING THE DNA REPAIR NETWORK IN CANCER DESCRIPTION: Genomic instability is a characteristic of cancer cells. Homologous recombination (HR)-mediated DNA repair represents an error-free repairing mechanism to maintain genomic integrity and ensure high-fidelity transmission of genetic information. My long-term goal is to establish a successful and sustainable independent research program with a core competency in the study of HR repair using genomic and proteomic approaches. In my independent career, I wish to pursue (1) fundamental studies to understand HR-mediated DNA repair and its dysfunction in tumorigenesis and (2) mechanism-based translational studies to translate fundamental breakthroughs in HR repair into clinical applications in cancer prevention, diagnosis, prognostication, and therapy. The overall objective of my proposed research, which will lay the foundation for my independent research career, is to understand the novel nuclear function of human Ago2, a core protein in RNA interference pathways, in HR repair and genome maintenance. Based on my preliminary data, I hypothesize that in the context of DNA damage response, via fine-tuned regulatory mechanisms by posttranslational modifications, potentially through ATM/ATR kinase-dependent phosphorylation, human nuclear Ago2 regulates HR repair of double-strand breaks by recruiting DNA repair proteins at damage sites via protein-protein interactions. I will test this hypothesis by pursuing 3 specific aims through an integrated platform that combines mechanistic and functional studies: (1) Determine the function of Ago2 as a novel regulator in HR repair. (2) Characterize posttranslational modifications of Ago2 induced by DNA damage in HR repair. (3) Determine the nuclear function of Ago2 in preventing genomic instability and tumorigenesis. The proposed research is significant because it challenges the current research paradigm that human Ago2 functions predominantly in the cytoplasm. This study will shed light on how 2 evolutionarily conserved genome defense mechanisms, the small regulatory RNA pathways and DNA damage response pathway, converge at DNA lesions in the process of HR repair via the functional involvement of Ago2 protein.