Understanding and Targeting the DNA Repair Network in Cancer

肿瘤DNA修复网络的研究进展 描述：基因组不稳定性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 长期目标是建立一个成功的和可持续的独立研究计划 在使用基因组和蛋白质组学研究HR修复方面具有核心竞争力 接近。在我独立的职业生涯中，我希望从事（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;（2） 以机制为基础的转化研究，转化人力资源的根本突破 在癌症预防、诊断、诊断和治疗中的临床应用， 疗法 我提出的研究的总体目标，这将奠定基础，我 独立的研究生涯，是为了了解人类Ago 2的新的核功能， RNA干扰途径、HR修复和基因组维持中的核心蛋白。 根据我的初步数据，我假设在DNA损伤反应的背景下， 通过翻译后修饰的微调调节机制， 通过ATM/ATR激酶依赖的磷酸化，人核Ago 2调节HR 通过在损伤位点募集DNA修复蛋白来修复双链断裂， 蛋白质相互作用我将通过追求3个具体目标来测试这个假设， 一个结合了机理和功能研究的综合平台：（1）确定 Ago 2作为一种新的调节剂在HR修复中的功能。(2)翻译后表征 在HR修复中由DNA损伤诱导的Ago 2修饰。(3)确定核 Ago 2在防止基因组不稳定性和肿瘤发生中的功能。拟议 研究是重要的，因为它挑战了目前的研究范式，人类 Ago 2主要在细胞质中发挥作用。这项研究将揭示如何2 进化上保守的基因组防御机制，小调控RNA 途径和DNA损伤反应途径，在DNA损伤的过程中会聚 通过Ago 2蛋白的功能参与HR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.