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FANCONI ANEMIA GENE PATHWAY IN RADIATION RESPONSES

辐射反应中的范可尼贫血基因途径

基本信息

批准号：
6690016
负责人：
LAWRENCE H THOMPSON
金额：
$ 36.47万
依托单位：
UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-24 至 2005-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6690016
关键词：
CHO cells DNA binding protein apoptosis cell growth regulation chromosome aberrations complementary DNA congenital aplastic anemia free radical oxygen gamma radiation gene induction /repression gene mutation human tissue hypoxanthine phosphoribosyltransferase immunocytochemistry oxidative stress radiation genetics yeast two hybrid system

项目摘要

The project's objective is to understand the molecular regulatory processes cells use to minimize genetic damage and genetic instability associated with reactive oxygen species (ROS) arising from endogenous processes or ionizing radiation (IR). This goal is addressed through studies of FANCG/XRCC9, the gene that is defective in. group G of the cancer-prone disorder Fanconi anemia (FA). Because FancG protein confers IR resistance in hamster cells, the human homolog is expected to participate in IR responses in human cells. Historically, a link between the FA genes and radiation responses has been unclear, with some studies suggesting that the primary defect in FA lies in removing DNA interstrand crosslinks. The general hypothesis to be tested is that the FANCG protein, as a member of a multiprotein complex, protects mammalian cells against endogenous and IR-generated oxidative damage and maintains genomic integrity by coordinating homeostasis processes that include regulation of ROS levels, apoptosis, and cell cycle progression. The proposed studies will provide a highly quantitative characterization of FANCG protein's contribution to biochemical and cellular endpoints associated with both normal cell proliferation and responses to IR exposure. Isogenic pairs of mutant and FANCG-complemented cells will be derived in both hamster CHO cells and human lymphoblasts. These pairs will be analyzed with respect to chromosomal aberrations, cell survival, hprt gene mutations, apoptosis, ROS, and cell cycle parameters with and without IR exposure. The FANCG-complemented FA-G lymphoblasts will be used to examine gene and protein regulation during the cell cycle as well as the subcellular localization of the protein with and without IR damage. Three proteins that are candidate interactors with FANCG from preliminary studies will be evaluated for possible involvement in the FA pathway. Finally, already identified high-frequency human allelic variants of FANCG in the US population will be evaluated for degree of dysfunction. The results of these studies will lead to more specific models of the nature of the FA protein "pathway" and its quantitative contributions to multiple biological effects associated with IR-mediated oxidative damage.

该项目的目标是了解细胞用于最大限度地减少与内源性过程或电离辐射（IR）产生的活性氧（ROS）相关的遗传损伤和遗传不稳定性的分子调控过程。这一目标是通过研究FANCG/XRCC 9来实现的，FANCG/XRCC 9是一种缺陷基因。 G组为易患癌症的Fanconi贫血（FA）。因为FancG蛋白在仓鼠细胞中赋予IR抗性，所以预期人同系物参与人细胞中的IR应答。从历史上看，FA基因和辐射反应之间的联系一直不清楚，一些研究表明FA的主要缺陷在于去除DNA链间交联。要测试的一般假设是，FANCG蛋白，作为一个多蛋白复合物的成员，保护哺乳动物细胞免受内源性和IR产生的氧化损伤，并保持基因组的完整性，通过协调稳态过程，包括调节ROS水平，细胞凋亡和细胞周期进程。拟议的研究将提供FANCG蛋白对与正常细胞增殖和对IR暴露的反应相关的生化和细胞终点的贡献的高度定量表征。将在仓鼠CHO细胞和人成淋巴细胞中衍生突变体和FANCG互补细胞的同基因对。将分析这些配对的染色体畸变、细胞存活、hprt基因突变、细胞凋亡、ROS和细胞周期参数（有和无IR暴露）。 FANCG补充的FA-G淋巴母细胞将用于检查细胞周期期间的基因和蛋白质调控以及有和无IR损伤的蛋白质的亚细胞定位。将评估来自初步研究的与FANCG相互作用的三种候选蛋白质是否可能参与FA途径。最后，将评价美国人群中已鉴定的FANCG高频人类等位基因变体的功能障碍程度。这些研究的结果将导致更具体的模型的性质的FA蛋白的“途径”和其定量贡献的多种生物学效应与IR介导的氧化损伤。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of the hamster FancG/Xrcc9 gene and mutations in CHO UV40 and NM3.

仓鼠 FancG/Xrcc9 基因的表征以及 CHO UV40 和 NM3 中的突变。

DOI：
10.1093/mutage/geh019
发表时间：
2004
期刊：
Mutagenesis
影响因子：
2.7
作者：
Lamerdin,JaneE;Yamada,NazumiA;George,JamesW;Souza,Brian;Christian,AllenT;Jones,NigelJ;Thompson,LarryH
通讯作者：
Thompson,LarryH

Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis.

Fanconi贫血途径的不同贡献和预防自发诱变的同源重组。

DOI：
10.1093/nar/gkm315
发表时间：
2007
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Hinz JM;Nham PB;Urbin SS;Jones IM;Thompson LH
通讯作者：
Thompson LH

Repression of mutagenesis by Rad51D-mediated homologous recombination.

DOI：
10.1093/nar/gkl020
发表时间：
2006
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Hinz JM;Tebbs RS;Wilson PF;Nham PB;Salazar EP;Nagasawa H;Urbin SS;Bedford JS;Thompson LH
通讯作者：
Thompson LH

Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability.

Fancg 基因在保护细胞免受颗粒铬酸盐诱导的染色体不稳定中的作用。

DOI：
10.1016/j.mrgentox.2006.09.005
发表时间：
2007
期刊：
Mutation research
影响因子：
0
作者：
Savery,LauraC;Grlickova-Duzevik,Eliza;Wise,SandraS;Thompson,WDouglas;Hinz,JohnM;Thompson,LarryH;WiseSr,JohnPierce
通讯作者：
WiseSr,JohnPierce

How Fanconi anemia proteins promote the four Rs: replication, recombination, repair, and recovery.

范可尼贫血蛋白如何促进 4 个 R：复制、重组、修复和恢复。