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Ubiquitin-Mediated Regulation of DNA Repair

泛素介导的 DNA 修复调节

基本信息

批准号：
7221197
负责人：
JAMES M. FORD
金额：
$ 27.99万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-07 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Nucleotide excision repair (NER) is a highly conserved DNA repair pathway that functions to protect the genome from the detrimental effects of DNA lesions introduced by endogenous and environmental sources, including UV light. Defects in the NER system result in genomic instability and the development of cancers. The initial step in NER requires lesion recognition, and is performed by the heterodimeric DNA damage binding proteins XPC-HR23B and UV-DDB (composed of the p48 and p127 proteins). The DDB2 (encoding the p48 protein) and XPC genes are transcriptionally induced by the p53 tumor suppressor gene following DNA damage. In addition, both p48 and XPC are post-translationally regulated by the ubiquitin-proteasome degradation pathway. Covalent attachment of mono- and polyubiquitin chains to cellular proteins has emerged as a predominant cellular regulatory mechanism with roles in cell division, signal transduction, endocytic trafficking, and DNA repair. Thus, the DNA damage recognition step of NER is highly regulated through transcriptional and post-transcriptional mechanisms. The long-term objectives of this project are to understand how the ubiquitin-proteasome pathway regulates human NER. The hypothesis is that UV-induced ubiquitination of the NER proteins t>48 and XPC specifically regulate their degradation, protein- and DNA damage binding activities, and affect on NER. These studies will have broad applicability to understanding the role of DNA repair in health and disease, and provide important insight into the role of NER in the etiology of human cancer. The project will be approached through the following specific aims. 1. To determine if the human DNA damage recognition factors p48 and XPC are ubiquitinated and if this process is regulated by HR23B. 2. To determine whether ubiquitination of these NER proteins is required for DNA damage binding activity, in vivo. 3. To determine the functional consequences of ubiquitination on NER activity in human cells.

描述（由申请人提供）：核苷酸切除修复（NER）是一种高度保守的DNA修复途径，其功能是保护基因组免受内源性和环境源（包括紫外线）引入的DNA损伤的有害影响。NER系统的缺陷导致基因组不稳定和癌症的发展。NER的第一步需要病变识别，由异二聚体DNA损伤结合蛋白XPC-HR23B和UV-DDB（由p48和p127蛋白组成）完成。DDB2（编码p48蛋白）和XPC基因在DNA损伤后被p53肿瘤抑制基因转录诱导。此外，p48和XPC均受泛素-蛋白酶体降解途径的翻译后调控。单和多泛素链与细胞蛋白的共价附着已成为一种主要的细胞调节机制，在细胞分裂、信号转导、内吞运输和DNA修复中发挥作用。因此，NER的DNA损伤识别步骤通过转录和转录后机制受到高度调控。该项目的长期目标是了解泛素-蛋白酶体途径如何调节人类NER。假设紫外线诱导的NER蛋白泛素化使bbbb48和XPC特异性调节其降解、蛋白和DNA损伤结合活性，并影响NER。这些研究将广泛适用于理解DNA修复在健康和疾病中的作用，并为NER在人类癌症病因学中的作用提供重要见解。该项目将通过以下具体目标进行。