"Roles of LIG3 and XRCC1 genes in genome stability".

描述（由申请人提供）：人类基因组受到内源性和环境DNA损伤剂的持续攻击。如果未修复，DNA损伤将引起突变，进而可能导致癌症形成。DNA修复途径的复杂网络起作用以去除DNA损伤。为了准确评估暴露于环境DNA损伤剂的生物学意义，有必要了解复杂的细胞对DNA损伤的反应的分子细节。虽然原核生物和低等真核生物已被证明是高等生物的有用模型系统，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、XRCC 1、聚（ADPribose）聚合酶-1（PARP-1）和DNA聚合酶β的基因的同源物。所有这些蛋白质都涉及DNA碱基切除修复和DNA单链断裂的修复。这项资助的目的是阐明LIG 3和XRCC 1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hRAD 50/Mre 11/Nbs复合物已被鉴定为体细胞中DNA连接酶III-α的伴侣。此外，DNA连接酶III-α已显示以细胞周期依赖性方式磷酸化，并响应于DNA损伤而去磷酸化。在此基础上，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MRE 11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）研究DNA连接酶III-α的功能和生物学后果。（iv）通过产生lig 3突变细胞系和动物来确定LIG 3基因产物的细胞功能。这些研究将提供新的见解，DNA交易是独特的更复杂的生物体，并将有助于DNA修复机制如何保护免受DNA损伤和突变引起的暴露于遗传毒性的环境因素的全貌。

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.