TULANE CANCER GENETICS COBRE: ATR KINASE AND UV-INDUCED CELL CYCLE CHECKPOINTS

杜兰大学癌症遗传学 COBRE：ATR 激酶和紫外线诱导的细胞周期检查点

• 批准号: 7382137
• 负责人: BO XU
• 金额: $ 27.56万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382137
• 关键词: TULANE; CANCER; GENETICS; COBRE; ATR

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell cycle checkpoints are among the mechanisms developed by eukaryotic cells to optimally respond to DNA damage agents, such as ionizing radiation (IR) and ultraviolet radiation (UV). These controllers of cell cycle progression presumably enhance genetic stability and limit tumorigenesis in the organism. Characterization of the biochemical steps in these signaling pathways will help improve our understanding of: 1) normal cell cycle control; and 2) mechanisms of cellular transformation following DNA damage. While IR-induced cell cycle checkpoints have been extensively studied, less is known about UV-induced cell cycle arrest. Our long term goal is to elucidate the signal transduction pathways that control UV-induced cell cycle checkpoints. Our preliminary observations suggest that the ATM-RAD3 related kinase, ATR, is required for UV-induced S-phase and G2/M checkpoints. ATR is a member of the phosphatidylinositol kinase related protein family that is essential for signaling the presence of DNA damage or replication blocks and activating cell cycle checkpoints. Since most of the DNA damage-induced signaling pathways consist of kinase-dependent signaling cascades that regulate cell cycle progression, we reason that ATR plays a central role in activation of UV-induced cell cycle checkpoints through phosphorylation of its downstream targets. We propose three specific aims to dissect the role of ATR in UV-induced cycle checkpoints. In Specific Aim 1, we will investigate whether BRCA1, NBS1 and SMC1 are involved in ATR-dependent S-phase arrest, and whether ATR phosphorylates these proteins to facilitate the arrest. In Specific Aim 2, we will investigate the biochemical linkage of ATR kinase and p38 MAP kinase in UV-induced G2 arrest. In specific Aim 3, we will investigate whether RAD 17 is a DNA damage sensor for recruiting ATR to regulate the checkpoints. These studies will provide novel insights into the roles and mechanisms of the ATR kinase and, in the process, should shed light on mechanisms involved in cell cycle control after environmental DNA damage.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。细胞周期检查点是真核细胞开发的机制之一，以最佳地响应DNA损伤剂，如电离辐射（IR）和紫外线辐射（UV）。这些细胞周期进程的控制器可能增强遗传稳定性并限制生物体中的肿瘤发生。对这些信号通路中的生化步骤进行表征将有助于提高我们对以下内容的理解：1）正常细胞周期控制;和2）DNA损伤后细胞转化的机制。虽然IR诱导的细胞周期检查点已被广泛研究，但对UV诱导的细胞周期停滞知之甚少。我们的长期目标是阐明控制紫外线诱导的细胞周期检查点的信号转导途径。我们的初步观察表明，ATM-RAD 3相关的激酶，ATR，需要紫外线诱导的S期和G2/M检查点。ATR是磷脂酰肌醇激酶相关蛋白家族的成员，其对于发出DNA损伤或复制阻断的存在的信号和激活细胞周期检查点是必需的。由于大多数的DNA损伤诱导的信号通路由激酶依赖的信号级联调节细胞周期的进展，我们的理由，ATR通过其下游靶点的磷酸化在紫外线诱导的细胞周期检查点的激活中起着核心作用。我们提出了三个具体的目标来剖析ATR在紫外线诱导的周期检查点的作用。在具体目标1中，我们将研究BRCA 1，NBS 1和SMC 1是否参与ATR依赖的S期阻滞，以及ATR是否磷酸化这些蛋白质以促进阻滞。在特定目标2中，我们将研究ATR激酶和p38 MAP激酶在UV诱导的G2期阻滞中的生物化学联系。在具体目标3中，我们将研究RAD 17是否是用于招募ATR来调节检查点的DNA损伤传感器。这些研究将为ATR激酶的作用和机制提供新的见解，并在此过程中揭示环境DNA损伤后细胞周期控制的机制。