Understanding and Targeting the DNA Repair Network in Cancer

描述（由申请人提供）：基因组不稳定性是癌细胞的一个特征。同源重组（Homologous recombination， HR）介导的DNA修复是一种无差错修复机制，可维持基因组完整性，确保遗传信息的高保真传递。我的长期目标是建立一个成功的、可持续的独立研究项目，在利用基因组和蛋白质组学方法研究HR修复方面具有核心竞争力。在我独立的职业生涯中，我希望进行(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)基于机制的转化研究，将HR修复的基础突破转化为癌症预防、诊断、预后和治疗的临床应用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed studies of Ago2 in HR repair will broaden our knowledge of this complex process and improve our understanding of how dysfunction of HR repair contributes to tumorigenesis. Elucidating the role of Ago2 in HR repair and tumorigenesis also may provide a molecular basis to expand the use of PARP inhibitors against tumors beyond BRCA1/BRCA2-deficient tumors.