Study of the clock-controlled DNA-damage response

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DESCRIPTION (provided by applicant): Circadian rhythms are the daily oscillation of various biological processes driven by the endogenous clock. Such rhythms include cell proliferation and DNA damage response. Disruption of circadian rhythm has been associated with human cancers and is one of the theoretical foundations for cancer chronotherapy. The circadian clock is operated by the interacting feedback loops of circadian genes that control downstream events by regulating clock-controlled genes. We have shown that the clock-controlled genes include those playing key roles in cell proliferation and DNA damage response. Mutation in one of the circadian genes, Period2, results in increased tumor development and deficient DNA damage response in mouse. The circadian clock, therefore, acts as a tumor suppressor in vivo. However, the current understanding on the mechanisms for the circadian clock to control cell cycle regulation and DNA damage response is still largely incomplete. Our tong-term goal is to understand the molecular mechanisms for the circadian clock to suppress malignant growth in vivo. In the near future, we will focus on studying the role of the molecular clock in DNA damage response. To reach this goal, our specific aims are: (1) to study the mechanisms of clock-controlled p53 induction after gamma-radiation. (2) to identify DNA damage response genes controlled directly by the molecular clock. These studies will contribute significantly to our understanding of the molecular mechanisms of cancer in vivo and will result in developing novel therapeutic strategies for cancer chronotherapy.