UNDERSTANDING AND TARGETING THE DNA REPAIR NETWORK IN CANCER: Genomic instability is a characteristic of cancer cells. Homologousrecombination (HR)-mediated DNA repair represents an error-free repairing mechanism tomaintain genomic integrity and ensure high-fidelity transmission of genetic information. Mylong-term goal is to establish a successful and sustainable independent research programwith a core competency in the study of HR repair using genomic and proteomicapproaches. In my independent career, I wish to pursue (1) fundamental studies tounderstand HR-mediated DNA repair and its dysfunction in tumorigenesis and (2)mechanism-based translational studies to translate fundamental breakthroughs in HRrepair into clinical applications in cancer prevention, diagnosis, prognostication, andtherapy.The overall objective of my proposed research, which will lay the foundation for myindependent 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, potentiallythrough ATM/ATR kinase-dependent phosphorylation, human nuclear Ago2 regulates HRrepair of double-strand breaks by recruiting DNA repair proteins at damage sites viaprotein-protein interactions. I will test this hypothesis by pursuing 3 specific aims throughan integrated platform that combines mechanistic and functional studies: (1) Determinethe function of Ago2 as a novel regulator in HR repair. (2) Characterize posttranslationalmodifications of Ago2 induced by DNA damage in HR repair. (3) Determine the nuclearfunction of Ago2 in preventing genomic instability and tumorigenesis. The proposedresearch is significant because it challenges the current research paradigm that humanAgo2 functions predominantly in the cytoplasm. This study will shed light on how 2evolutionarily conserved genome defense mechanisms, the small regulatory RNApathways and DNA damage response pathway, converge at DNA lesions in the processof HR repair via the functional involvement of Ago2 protein.