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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

基本信息

批准号：
8433258
负责人：
Xinbin Chen
金额：
$ 26.22万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/8433258
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

项目摘要

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.

DNA聚合酶eta在DNA损伤反应和p53激活中的作用提出本申请以解决DNA聚合酶eta（PolH）的信号传导途径， DNA损伤反应与p53激活及p53与p53信号通路相互作用的影响 PolH对细胞存活和死亡的影响。为了描述p53在DNA损伤反应中的作用，我们发现PolH可以由DNA损伤以p53依赖的方式诱导。PolH是一种着色性干皮病（XP）基因。XP是一种常染色体隐性遗传疾病，XP患者容易出现恶性皮肤癌的早期发病。有趣的是，我们发现敲低PolH可以增强细胞的增殖，通过抑制DNA损伤诱导的细胞凋亡而存活。我们还发现，DNA损伤诱导在PolH敲低和PolH缺失细胞中，p53的激活都受到损害，这可以通过以下方法来挽救：重组PolH。此外，我们发现PolH通过ATM调节DNA损伤反应， ChK 2-p53通路。最后，我们最近的初步研究表明，PolH蛋白的稳定性是 PolH与Mdm 2和Pirh 2发生物理相互作用，两者都是p53 靶基因和E3连接酶。综上所述，我们假设PolH活性受到多种因素的调节， PolH在DNA损伤反应和p53激活中具有新的功能。以进一步解决为此，提出了以下三个具体目标：（1）确定PolH表达是否以及如何在基础和DNA损伤条件下调节;（2）确定 PolH与Mdm 2或Pirh 2之间的相互作用;（3）确定PolH在DNA损伤中的作用反应和p53激活。