DNA damage response and DDB

DNA损伤反应和DDB

基本信息

批准号：
7603020
负责人：
Pradip Raychaudhuri
金额：
$ 28.05万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7603020
关键词：
1-Phosphatidylinositol 3-Kinase 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide Adult Aging Alkylating Agents Alleles Ataxia-Telangiectasia-Mutated protein kinase Binding CDT1 Gene Cell Aging Cell Cycle Cell Cycle Progression Cell Line Cells Checkpoint kinase 1 Chromatin Cisplatin Complex Cyclophosphamide DNA DNA Damage DNA Repair DNA biosynthesis DNA lesion DNA-Binding Proteins Disease E1A-associated p300 protein EP300 gene Embryo Exhibits Fibroblasts Fission Yeast Genes Genetic Genetic Transcription Hand Incidence JUN gene Knock-out Link Malignant Neoplasms Mediating Methyl Methanesulfonate Mouse Strains Mus Mutation Pathway interactions Peptide Initiation Factors Phase Phosphotransferases Physiological Play Principal Investigator Process Proteolysis Proto-Oncogene Proteins c-jun Recruitment Activity Replication Initiation Reporting Role Signal Pathway Signal Transduction Somatic Cell Specificity Stress System TP53 gene Testing Time Tissues Tobacco Ubiquitin Ubiquitination Xenopus oocyte Yeasts age related base chromatin remodeling complement deficiency cullin 4A genetic regulatory protein in vivo insight multicatalytic endopeptidase complex programs recombinase repaired response senescence sensor temperature sensitive mutant tissue regeneration tumor ubiquitin-protein ligase ultraviolet damage ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): DNA damage in somatic cells is one of the main causes of aging and many age-related diseases, including cancer and decreased tissue regeneration. Cells respond to DNA damage by triggering the checkpoint pathways that delay the cell cycle progression allowing time for DNA repair. The checkpoint pathway involves association of the PI3 kinases ATM/ATR with damaged chromatin and subsequent activation of the checkpoint kinases (Chk1 and Chk2) and p53, as well as other regulatory proteins that control the fate of a cell following DNA damage. Despite significant advances on the damage-response pathways, the mechanisms (sensors) that recruit ATM/ATR to damaged-DNA are not known. Our recent studies revealed that the damaged-DNA binding protein DDB functions as a damage-sensor that recruits ATR to the UV-damaged chromatin to activate the ATR-Chk1/p53 pathway. The objectives of this proposal are to further investigate the damage-sensor function of DDB and determine the spectrum of DNA damage for which DDB functions as a sensor leading to the activation of the ATR-checkpoint pathway. DDB is composed to two subunits: DDB1 and DDB2. The DDB2 subunit is transcriptionally induced by p53 upon DNA damage. We will test the hypothesis that the p53-induced expression of DDB2 is critical for a sustained activation of the checkpoints following DNA damage. Also, we plan to develop a knockout strain of mice lacking DDB1 to investigate the functions of DDB1 in a physiological context. Accumulating evidence indicates that the DDB1 subunit possesses functions that are independent of the DDB2 subunit. For example, DDB1 has been shown to be involved in the proteolysis of c-jun in conjunction with cullin 4A. Also, the fission yeast ortholgue of DDB1 has been implicated in the proteolysis through the ubiquitin-proteasome pathway. A conditional knockout strain of mice will be important in evaluating the various functions of DDB1 in a physiological context. The specific aims are: 1. Does DDB function as a sensor for a wide range of DNA damages? Is the DDB-mediated activation of ATR-Chk1 linked to initiation of DNA replication? Does the DDB-mediated activation of ATR-Chk1 involve chromatin-remodeling by CBP/p300? 2.Does DDB play a role in the sustained activation of checkpoints following DNA damage? Does DNA damage-induced senescence depend upon DDB? 3. What are the in vivo functions of DDB1?

描述（由申请人提供）：体细胞中的DNA损伤是衰老和许多与年龄有关的疾病的主要原因之一，包括癌症和组织再生。细胞通过触发延迟细胞周期进程的检查点途径来应对DNA损伤，从而允许DNA修复时间。检查点途径涉及将PI3激酶ATM/ATR与染色质受损的关联以及随后的检查点激酶（CHK1和CHK2）和p53的激活，以及其他调节蛋白，这些调节蛋白控制DNA损伤后细胞的命运。尽管损伤响应途径取得了重大进展，但尚不清楚将ATM/ATR募集到损坏的DNA的机制（传感器）。我们最近的研究表明，受损的DNA结合蛋白DDB充当损伤传感器，可募集ATR到UV受损的染色质中，以激活ATR-CHK1/p53途径。该建议的目标是进一步研究DDB的损伤传感器功能，并确定DNA损伤的频谱DDB充当传感器，导致ATR-Checkpoint途径的激活。 DDB组成两个亚基：DDB1和DDB2。 DDB2亚基是在DNA损伤后通过p53转录诱导的。我们将测试以下假设：p53诱导的DDB2表达对于DNA损伤后的检查点的持续激活至关重要。此外，我们计划开发缺乏DDB1的小鼠的敲除菌株，以研究生理环境中DDB1的功能。积累的证据表明DDB1亚基具有与DDB2亚基无关的功能。例如，DDB1已显示与C-Jun与Cullin 4A结合使用。同样，DDB1的裂变酵母正矫正与通过泛素 - 蛋白酶体途径的蛋白水解有关。小鼠的条件敲除菌株对于在生理环境中评估DDB1的各种功能将很重要。具体目的是： 1。DDB是否充当多种DNA损伤的传感器？ DDB介导的ATR-CHK1的激活是否与DNA复制的启动有关？ DDB介导的ATR-CHK1激活是否涉及CBP/P300的染色质复制？ 2. DYES DDB在DNA损伤后的检查点的持续激活中起作用吗？ DNA损伤引起的衰老是否取决于DDB？ 3。DDB1的体内功能是什么？