The role of DNA polymerase eta in DNA damage response and p53 activation

DNA聚合酶eta在DNA损伤反应和p53激活中的作用

• 批准号: 8035416
• 负责人: Xinbin Chen
• 金额: $ 27.77万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035416
• 关键词: Address; Apoptosis; Bypass; Carcinogens; Cell Death; Cell Survival; Cells; DNA Damage; DNA biosynthesis; DNA lesion; DNA-Directed DNA Polymerase; Degradation Pathway; Development; Disease; Double Strand Break Repair; Exhibits; Family; Frequencies; Gene Targeting; Genes; Genomic Instability; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Modification; Mono-S; Nucleotide Excision Repair; Null Lymphocytes; Pathway interactions; Patients; Play; Protein p53; Proteins; Pyrimidine Dimers; Rad30 protein; Role; Signal Pathway; Sister Chromatid Exchange; Skin Cancer; TP53 gene; Treatment Efficacy; Tumor Suppressor Proteins; UV induced; Ubiquitination; Variant; Xeroderma Pigmentosum; early onset; homologous recombination; novel; prevent; public health relevance; reconstitution; repaired; response; tumor initiation; tumor progression; ubiquitin-protein ligase; ultraviolet irradiation

DESCRIPTION (provided by applicant): The role of DNA polymerase eta in DNA damage response and p53 activation. This application is proposed to address the signaling pathway of DNA polymerase eta (PolH) in DNA damage response and p53 activation and the effect of the signal pathway interaction between p53 and PolH on cell survival and death. In an effort to characterize the role of p53 in DNA damage response, we found that PolH can be induced by DNA damage in a p53-dependent manner. PolH is the product of the Xeroderma Pigmentosum (XP) gene. XP is an autosomal recessive disorder, and XP patients are prone to early onset of malignant skin cancers. Interestingly, we found that knockdown of PolH enhances cell survival by inhibiting DNA damage-induced apoptosis. We also found that DNA damage-induced activation of p53 is impaired in both PolH-knockdown and PolH-null cells, which can be rescued by a reconstituted PolH. Furthermore, we found that PolH modulates DNA damage response via the ATM- ChK2-p53 pathway. Finally, our recent preliminary studies showed that the stability of PolH protein is decreased upon DNA damage and PolH physically interacts with Mdm2 and Pirh2, both of which are a p53 target gene and an E3 ligase. Taken together, we hypothesize that PolH activity is regulated by multiple pathways and PolH has novel functions in DNA damage response and p53 activation. To further address this, the following three specific aims are proposed: (1) to determine whether and how PolH expression is regulated at basal and DNA damage conditions; (2) to determine the functional significance of the interaction between PolH and Mdm2 or Pirh2; and (3) to determine the role of PolH in DNA damage response and p53 activation.

描述（由申请人提供）：DNA聚合酶ETA在DNA损伤反应和p53激活中的作用。 提出了该应用来解决DNA聚合酶ETA（POLH）在DNA损伤反应和p53激活中的信号传导途径，以及p53和Polh之间信号途径相互作用对细胞存活和死亡的影响。为了表征p53在DNA损伤反应中的作用，我们发现Polh可以通过p53依赖性方式通过DNA损伤诱导。 polh是心胚层色素（XP）基因的乘积。 XP是一种常染色体隐性疾病，XP患者容易早期发作恶性皮肤癌。有趣的是，我们发现Polh的敲低通过抑制DNA损伤诱导的凋亡来增强细胞的存活。我们还发现，在Polh-Knockdown和Polh-Null细胞中，DNA损伤诱导的p53激活受损，可通过重构Polh挽救。此外，我们发现Polh通过ATM-CHK2-P53途径调节DNA损伤响应。最后，我们最近的初步研究表明，在DNA损伤时polh蛋白的稳定性降低，Polh与MDM2和PIRH2物理相互作用，这两者都是p53靶基因和E3连接酶。综上所述，我们假设Polh活性受多种途径调节，Polh在DNA损伤反应和p53激活中具有新的功能。为了进一步解决这一问题，提出了以下三个特定目标：（1）确定在基础和DNA损伤条件下Polh表达是否以及如何调节； （2）确定Polh和MDM2或PIRH2之间相互作用的功能意义； （3）确定polh在DNA损伤反应和p53激活中的作用。