Study of the clock-controlled DNA-damage response

描述(由申请人提供)： 昼夜节律是由内源性时钟驱动的各种生物过程的每日振荡。这种节律包括细胞增殖和DNA损伤反应。昼夜节律紊乱与人类癌症有关，是癌症计时疗法的理论基础之一。生物钟由昼夜节律基因的相互作用的反馈环控制，这些反馈环通过调节钟控基因来控制下游事件。我们已经证明，时钟控制的基因包括那些在细胞增殖和DNA损伤反应中发挥关键作用的基因。其中一个昼夜节律基因Perio2的突变会导致小鼠肿瘤发展加速和DNA损伤反应不足。因此，生物钟在体内扮演着肿瘤抑制者的角色。然而，目前对生物钟控制细胞周期调控和DNA损伤反应的机制的了解还很不完整。我们的长期目标是了解生物钟抑制体内恶性生长的分子机制。在不久的将来，我们将重点研究分子时钟在DNA损伤反应中的作用。为实现这一目标，我们的具体目标是： (1)研究辐射后钟控P53基因的诱导机制。 (2)寻找由分子钟直接控制的DNA损伤反应基因。 这些研究将有助于我们了解癌症在体内的分子机制，并将导致开发新的治疗策略的癌症时间治疗。

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.