Radiation-induced ATM and ERK signaling in DSB repair

描述（由申请人提供）：ATM调节许多细胞过程，包括DNA损伤反应和DNA双链断裂（DSB）修复，以及涉及氧化应激和细胞生长的反应。许多与ATM相关的由辐射触发的过程已经被描述和表征。然而，ATM平衡生长和评估DNA损伤（和其他压力）以及帮助细胞决定生存和死亡的能力的机制相对未知。我们最近报道了一个有趣的观察结果，即在对辐射的反应中，ATM和促生存MEK/ERK信号传导形成了一个调节同源重组修复的反馈环- ATM调节ERK磷酸化（从而激活），而MEK/ERK是ATM在丝氨酸-1981处磷酸化所必需的。这两种机制目前都不清楚。在此，我们建议确定这两个过程的机制，以及ATM和MEK/ERK信号在调节非同源末端连接（NHEJ）中的作用，特别是，ATM和MEK/ERK信号是否控制DNA修复保真度在这个系统中。我们的研究将集中在寻找生长因子受体和PI 3 K/AKT存活信号之间的可能联系以及调节NHEJ质量的能力上。更好地理解这些过程是很重要的，因为关于细胞平衡细胞生长与癌症应激反应的能力的信息很少，特别是它与DSB修复的关系。这些信息可能被用于改善癌症治疗。公共卫生相关性：关于细胞在癌症中平衡细胞生长与应激反应的能力，特别是它与DNA修复的关系，几乎没有信息。由ATM控制的生长和应激之间的动态相互作用是重要的，并且可以用于改善癌症治疗。

DESCRIPTION (provided by applicant): ATM regulates many cellular processes including DNA damage responses and DNA double-strand break (DSB) repair in addition to responses involving oxidative stress and cell growth. Many of the processes ATM are associated with that are triggered by radiation have been described and characterized. However, the mechanisms involved in ATM's ability to balance growth and assess DNA damage (and other stresses) and help the cell decide between survival and death are relatively unknown. We have recently reported on the interesting observation that in response to radiation, ATM and prosurvival MEK/ERK signaling forms a feedback loop that regulates homologous recombination repair - ATM regulates ERK phosphorylation (and thus activation) whereas MEK/ERK is required for phosphorylation of ATM at serine-1981. Neither mechanism is presently known. Herein, we propose to determine the mechanisms of both these processes as well as the role of ATM and MEK/ERK signaling in regulating non-homologous end-joining (NHEJ), and, in particular, whether ATM and MEK/ERK signaling control DNA repair fidelity in this system. We will focus our studies on finding possible links between growth factor receptor and PI3K/AKT survival signaling and the ability to modulate the quality of NHEJ. A better understanding of these processes is important since there is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DSB repair. This information might be utilized for improving cancer therapy. PUBLIC HEALTH RELEVANCE: There is little information available regarding the cell's ability to balance cellular growth with stress responses in cancer, in particular how it relates to DNA repair. The dynamic interaction between growth and stress that is controlled by ATM is important and might be utilized for improving cancer therapy.