In vivo misregulation of genes involved in apoptosis, development and oxidative stress in mice lacking both functional Werner syndrome protein and poly(ADP-ribose) polymerase-1
In vivo misregulation of genes involved in apoptosis, development and oxidative stress in mice lacking both functional Werner syndrome protein and poly(ADP-ribose) polymerase-1
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DOI：
10.1093/hmg/ddi362
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Lebel, M
中科院分区：
文献类型：
--
作者：
Deschênes, F;Massip, L;Lebel, M
沃纳综合征（WS）是一种罕见的疾病，其特征是许多年龄相关疾病的过早发作。导致WS的基因被认为参与了转录、复制和/或DNA修复的不同方面。聚（adp -核糖）聚合酶-1 （PARP-1）酶也参与DNA修复，并已知影响几种基因的转录。在这项研究中，我们检测了缺乏其中一种或两种酶正常功能的细胞的表达谱。所有突变细胞都表现出对氧化应激正常反应的基因表达改变。有趣的是，在双突变细胞中发现的超过58%的失调基因在单独携带Wrn或PARP-1突变的细胞中没有改变。因此，Wrn和PARP-1同时突变对基因表达谱的影响大于单个突变基因型的简单添加。此外，培养的双突变细胞在细胞凋亡、细胞周期控制、胚胎发育、代谢和信号转导等相关基因中表现出严重的失调。更重要的是，双突变小鼠的体内分析证实了胚胎中细胞凋亡和发育缺陷的增加，以及成年组织中细胞内磷酸化和DNA氧化损伤的增加。随着年龄的增长，他们的氧化应激也逐渐增加。因此，本研究的一个主要结果是，体外鉴定的几种基因表达和生理功能的变化在小鼠胚胎和成年组织中得到了证实。
Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication and/or DNA repair. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme is also involved in DNA repair and is known to affect transcription of several genes. In this study, we examined the expression profile of cells lacking the normal function of either or both enzymes. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. Interestingly, more than 58% of misregulated genes identified in double mutant cells were not altered in cells with either the Wrn or PARP-1 mutation alone. So, the impact on gene expression profile when both Wrn and PARP-1 are mutated was greater than a simple addition of individual mutant genotype. In addition, double mutant cultured cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism and signal transduction. More importantly, in vivo analyses of double mutant mice have confirmed the increased apoptosis and the developmental defects in embryos as well as the major increase in intracellular phosphorylation and oxidative DNA damage in adult tissues. They also exhibited a progressive increase in oxidative stress with age. Thus, a major result of this study is that changes in expression of several genes and physiological functions identified in vitro were confirmed in mouse embryonic and adult tissues.