Radiation-induced ATM and ERK signaling in DSB repair

描述(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。已经描述和表征了由辐射触发的与ATM相关联的许多过程。然而，ATM平衡生长和评估DNA损伤(和其他压力)以及帮助细胞在生存和死亡之间做出决定的能力所涉及的机制相对未知。我们最近报道了一项有趣的观察，在辐射反应中，ATM和存续的MEK/ERK信号形成了一个调节同源重组修复的反馈环-ATM调节ERK的磷酸化(从而激活)，而MEK/ERK是ATM在1981年丝氨酸磷酸化所必需的。这两种机制目前都不为人所知。在这里，我们建议确定这两个过程的机制以及ATM和MEK/ERK信号在调控非同源末端连接(NHEJ)中的作用，特别是ATM和MEK/ERK信号是否控制该系统中的DNA修复保真度。我们的研究将集中在寻找生长因子受体与PI3K/AKT生存信号之间的可能联系以及调节NHEJ质量的能力。更好地了解这些过程是重要的，因为关于细胞平衡细胞生长和癌症应激反应的能力，特别是它与DSB修复的关系，可用的信息很少。这一信息可能被用来改进癌症治疗。与公共健康相关：关于细胞在癌症中平衡细胞生长和应激反应的能力，特别是它与DNA修复的关系，可用的信息很少。ATM控制的生长和压力之间的动态相互作用是重要的，可能被用来改进癌症治疗。

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.