Novel roles for the DNA damage response kinase CHK1 in TCR/ITAM signaling

项目概要 协调 DNA 损伤反应的细胞机制对于确保细胞 具有潜在有害缺陷的细胞不会在细胞周期中进展并促进恶性转化。 为此，ATR 激活的 CHK1 激酶在细胞核中识别复制时具有关键功能 通过触发停止细胞周期的信号级联，对停滞的 DNA 复制叉施加压力。然而， 该激酶对在细胞核外的作用尚不清楚，并且特定于的非规范功能 之前尚未探索过免疫反应。采用尖端生物化学、超分辨率 成像、细胞和体内免疫学方法，将追求两个具体目标。目标 1) 定义 CHK1 和 T 细胞受体 (TCR) 信号分子之间的分子联系及其在 T 细胞中的作用 体内激活。目标 2) 评估 CHK1 在免疫相关受体中的类似信号传导作用 以便查明其作用机制。这些研究预计将对角色产生基本的见解 对于 CHK1，迄今为止推测主要在细胞核、细胞质免疫受体信号传导中发挥作用 事件并定义这些作用对免疫力的影响。这些研究的更广泛的影响包括新颖的 深入了解 ATR 和 CHK1 抑制剂的潜在影响（目前正在癌症临床试验中进行评估） 免疫系统。这些见解可能有助于减轻这些药物的意外影响， 最大限度地发挥 ATR/CHK1 或新型下游介质治疗疾病的潜力 免疫系统。 ！

Project Summary The cellular machinery coordinating responses to DNA damage is critically important to ensure that cells with potentially deleterious defects do not progress through the cell cycle and promote malignant transformation. To this end, the ATR-activated CHK1 kinase has key functions in the nucleus upon recognition of replication stress at stalled DNA replication forks by triggering a signaling cascade that halts the cell cycle. However, the roles for this kinase pair outside the nucleus are less well understood, and a non-canonical function specific to the immune response has not been explored previously. Using cutting-edge biochemistry, super-resolution imaging, and cellular and in vivo immunology approaches, two specific aims will be pursued. Aim 1) To define the molecular connections between CHK1 and T cell receptor (TCR) signaling molecules and their roles in T cell activation in vivo. Aim 2) To evaluate analogous signaling roles for CHK1 in related receptors of the immune in order to pinpoint its mechanism of action. These studies are expected to yield fundamental insights into roles for CHK1, heretofore presumed to function primarily in the nucleus, in cytoplasmic immunoreceptor signaling events and define the impact of these roles on immunity. The broader implications of these studies include novel insights into potential effects of ATR and CHK1 inhibitors, currently under evaluation in cancer clinical trials, on the immune system. These insights may be beneficial in mitigating unexpected effects of these drugs and maximizing the potential to target ATR/CHK1 or novel downstream mediators therapeutically in diseases of the immune system. !