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.

Public Health Relevance

UNDERSTANDING AND TARGETING THE DNA REPAIR NETWORK IN CANCER 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA149186-04
Application #
8618778
Study Section
Special Emphasis Panel (NSS)
Program Officer
Pelroy, Richard
Project Start
2011-07-18
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$183,251
Indirect Cost
$79,459
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Peng, Guang; Woodman, Scott E; Mills, Gordon B (2014) RADical response puts an exceptional responder in CHKmate: a synthetic lethal curative response to DNA-damaging chemotherapy? Cancer Discov 4:988-90
Peng, Guang; Chun-Jen Lin, Curtis; Mo, Wei et al. (2014) Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat Commun 5:3361