Regulation of ATM- and ATR-related protein kinases

染色体不断受到外源性和内源性威胁的挑战。因此，受损DNA的修复对于维持基因组稳定性至关重要。不适当的DNA损伤反应诱导基因组不稳定性，导致癌症的发展。为了保持基因组的完整性，所有生物都通过迅速启动DNA损伤反应来应对DNA损伤。这种反应涉及DNA修复因子到DNA损伤位点的募集和信号转导途径的激活，通常称为DNA损伤检查点途径。 检查点信号传导需要两种进化上保守的磷脂酰肌醇3-激酶（Pl3K）相关蛋白激酶：ATM和ATR。虽然ATM主要对DNA双链断裂作出反应，但ATR识别具有单链DNA的各种类型的DNA损伤。在芽殖酵母酿酒酵母中，ATM和ATR分别对应于Tel 1和Mec 1。 该项目的长期目标是揭示Mec1和Tel 1如何促进基因组稳定性维持的调控机制。在这项提案中，我们计划揭示Mec1如何激活DNA损伤检查点通路（Aim 1）的分子细节，并定义Tel 1如何刺激DNA损伤信号传导并调节DNA断裂修复（Aim 2）。我们还将确定Mec1和Tel 1如何进行蛋白质成熟（目的3）。鉴于DNA修复和检查点蛋白的进化保守性，我们使用芽殖酵母的研究将为了解人类ATM和ATR如何激活检查点信号并控制DNA损伤反应提供宝贵的信息。由于不适当的DNA损伤反应和突变积累与癌症发生和细胞衰老有关，我们的研究将有助于开发更好的癌症治疗和预防过早衰老。

Chromosomes are constantly challenged by exogenous and endogenous threats. The repair of damaged DNAs is therefore crucial for maintaining genome stability. Improper DNA damage response induces genomic instability, resulting in cancer development. To maintain genomic integrity, all organisms respond to DNA damage by promptly launching the DNA-damage response. This response involves the recruitment of DNA repair factors to sites of DNA damage and the activation of signal transduction pathways, often termed DNA-damage checkpoint pathways. Checkpoint signaling requires two evolutionarily conserved phosphatidylinositol 3-kinase (Pl3K)-related protein kinases: ATM and ATR. While ATM responds primarily to DNA double-strand breaks, ATR recognizes various types of DNA lesions with single-stranded DNA. In the budding yeast Saccharomyces cerevisiae ATM and ATR correspond to Tel1 and Mec1, respectively. The long-term goal of this project is to uncover the regulatory mechanism of how Mec1 and Tel1 contribute to genome stability maintenance. In this proposal, we plan to uncover the molecular detail of how Mec1 activates the DNA damage checkpoint pathway (Aim 1), and define how Tel1 stimulates DNA damage signaling and regulates DNA break repair (Aim 2). We will also determine how Mec1 and Tel1 undergo protein maturation (Aim 3). Given the evolutionary conservation of DNA repair and checkpoint proteins, our study using budding yeast will provide invaluable information to understand how human ATM and ATR activates checkpoint signaling and controls DNA damage responses. Since improper DNA damage response and mutation accumulation are implicated in carcinogenesis and cell senescence, our study will contribute to the development of better cancer treatment and the prevention of premature aging.