Roles of LIG3 and XRCC1 genes in genome stability.

LIG3 和 XRCC1 基因在基因组稳定性中的作用。

基本信息

批准号：
7393111
负责人：
Alan E Tomkinson
金额：
$ 29.07万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2004-04-22 至 2009-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7393111
关键词：
Animals Apoptosis BRCT Domain Base Excision Repairs Biological Biological Models C-terminal Catalytic Domain Cell Cycle Cell Cycle Checkpoint Cell Line Cell physiology Complex DNA DNA Damage DNA Ligases DNA Polymerase beta DNA Repair DNA Repair Pathway DNA Sequence Rearrangement DNA Single Strand Break DNA biosynthesis DNA lesion DNA ligase III DNA strand break DNA-Directed DNA Polymerase Defect Enzymes Eukaryota Eukaryotic Cell Exposure to Genes Genome Stability Genomic Instability Genomics Goals Grant Homologous Gene Human Genome Hypersensitivity Induced Mutation LIG4 gene Laboratories Lead Malignant Neoplasms Mammalian Cell Mediating Metabolism Modification Molecular Mutation N-terminal Organism Poly(ADP-ribose) Polymerases Process Prokaryotic Cells Proteins Reaction Role Somatic Cell Structure XRCC1 gene base environmental agent insight mutant novel polypeptide prevent recombinational repair repaired response

项目摘要

DESCRIPTION (provided by applicant): The human genome is subject to constant attack by endogenous and environmental DNA damaging agents. If unrepaired, DNA lesions will give rise to mutations that in turn may lead to cancer formation. A complex network of DNA repair pathways operates to remove DNA lesions. In order to accurately assess the biological significance of exposure to environmental DNA damaging agents, it is necessary to understand the molecular details of the complex cellular response to DNA damage. Although prokaryotes and lower eukaryotes have proven to be useful model systems for higher organisms, there are aspects of the DNA response, including DNA repair pathways that appear to be restricted to higher eukaryotes. For example, lower eukaryotes lack homologs of the genes encoding DNA ligase III, XRCC1, poly (ADPribose) polymerase-1 (PARP-1) and DNA polymerase beta. All of these proteins have been implicated in DNA base excision repair and the repair of DNA single-strand breaks. The goal of this grant is to elucidate the roles of the LIG3 and XRCC1 gene products in maintaining genome stability in mammalian cells. In preliminary studies, PARP-1 and the hRAD50/Mre11/Nbs complex have been identified as partners of DNA ligase III-alpha in somatic cells. In addition, DNA ligase III-alpha has been shown to be phosphorylated in a cell-cycle dependent manner and dephosphorylated in response to DNA damage. On the basis of these results, 4 aims are proposed: (i) to delineate the functional and biological consequences of the interaction between DNA ligase III-alpha and PARP-1; (ii) to elucidate the functional and biological consequences of the interaction between DNA ligase III-alpha and the MRE11 complex; (iii) to characterize cell cycle-regulated and DNA damage-dependent modifications of DNA ligase III-alpha; (iv) to determine the cellular functions of the LIG3 gene products by generating lig3 mutant cell lines and animals. These studies will provide novel insights into DNA transactions that are unique to more complex organisms and will contribute to an overall picture of how DNA repair mechanisms protect against DNA damage and mutations induced by exposure to genotoxic environmental agents.

描述（由申请人提供）：人类基因组不断受到内源性和环境性 DNA 损伤剂的攻击。如果不加以修复，DNA 损伤将引起突变，进而可能导致癌症的形成。 DNA 修复途径的复杂网络可消除 DNA 损伤。为了准确评估暴露于环境 DNA 损伤剂的生物学意义，有必要了解细胞对 DNA 损伤的复杂反应的分子细节。尽管原核生物和低等真核生物已被证明是高等生物体的有用模型系统，但 DNA 反应的某些方面（包括 DNA 修复途径）似乎仅限于高等真核生物。例如，低等真核生物缺乏编码DNA连接酶III、XRCC1、聚(ADP核糖)聚合酶-1 (PARP-1)和DNA聚合酶β的基因的同源物。所有这些蛋白质都与 DNA 碱基切除修复和 DNA 单链断裂修复有关。这笔资助的目的是阐明 LIG3 和 XRCC1 基因产物在维持哺乳动物细胞基因组稳定性中的作用。在初步研究中，PARP-1 和 hRAD50/Mre11/Nbs 复合物已被确定为体细胞中 DNA 连接酶 III-α 的伴侣。此外，DNA 连接酶 III-α 已被证明以细胞周期依赖性方式磷酸化，并响应 DNA 损伤而去磷酸化。基于这些结果，提出了 4 个目标：(i) 描述 DNA 连接酶 III-α 和 PARP-1 之间相互作用的功能和生物学后果； (ii) 阐明 DNA 连接酶 III-α 和 MRE11 复合物之间相互作用的功能和生物学后果； (iii) 表征 DNA 连接酶 III-α 的细胞周期调节和 DNA 损伤依赖性修饰； (iv)通过产生lig3突变细胞系和动物来确定LIG3基因产物的细胞功能。这些研究将为更复杂的生物体特有的DNA交易提供新的见解，并将有助于全面了解DNA修复机制如何防止因暴露于基因毒性环境因素而引起的DNA损伤和突变。