ATM, P53, GADD45 AND P21 EFFECTS ON RECOMBINATION

ATM、P53、GADD45 和 P21 对重组的影响

• 批准号: 6447049
• 负责人: ROBERT H SCHIESTL
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447049
• 关键词: DNA damage; DNA repair; adduct; antioxidants; carcinogenesis; cell cycle proteins; crosslink; gene deletion mutation; gene expression; gene induction /repression; genetic recombination; ionizing radiation; laboratory mouse; nucleic acid sequence; nutrition related tag; oxidative stress; p53 gene /protein

DNA lesions such as double-stranded breaks (DSBs), DNA adducts and DNA strand cross links cause cancer. Such lesions may result in cell cycle arrest and if repairable, initiate repair reactions including recombination which may lead to genomic rearrangements. The following genes may be involved in DNA damage detection or processing and executing cellular responses. ATM may signal the presence of DNA damage, p53 activates transcription of p21 and Gadd45, which are involved in cell cycle arrest, stopping DNA synthesis in response to the damage and in coordinating repair reactions. Mouse models lacking these genes have been developed. Genome rearrangements such as deletions are associated with carcinogenesis. We have previously shown that X-rays, benzo(a)pyrene (B(a)P) and cisplatin cause DNA DSBs, DNA adducts and DNA cross links respectively increase the frequency of deletions between repeated DNA sequences in the mouse genome. Disruption of the p gene by a DNA duplication, the p/un mutation, results in a diluted coat color and pink eyes. The reversion of this duplication to wildtype in the embryo results in black spots on the fur and the retinal pigment epithelium in the eyes. We have previously shown p53 is involved in X-ray but not in B(a)P induced p/un reversions. Furthermore, X-rays but not B(a)P acts in a p53 independent manner. X-rays induce p53 in an ATM dependent way and in contrast, cisplatin induces p53 in an ATM independent way. These carcinogens will be used to dissect the ATM/p53/p21/Gadd45 DNA damage recognition and repair in mouse embryos. These data will be correlated with induction profiles of these gene products induced by the carcinogenesis in embryos. It has also been proposed that oxidative stress plays a role in the pathogenesis of AT. We propose to determine whether oxidative stress is involved in any different responses of ATM mice to ionizing radiation and we will determine whether nutritional factors such as pro-oxidants and anti-oxidants have any effect on such oxidative stress parameters. If the frequency of deletions in ATM deficient mice can be reduced by exposure to antioxidants this may indicate that oxidative stress may at least partially be responsible for the high incidence of carcinogenesis which in turn may raise the possibility of intervention with nutritional antioxidants.

DNA损伤，如双链断裂（DSB），DNA加合物和DNA链交联导致癌症。这样的损伤可能导致细胞周期停滞，并且如果是可修复的，则启动修复反应，包括可能导致基因组重排的重组。以下基因可能参与DNA损伤检测或处理和执行细胞反应。ATM可能是DNA损伤的信号，p53激活p21和Gadd 45的转录，这两个基因参与细胞周期停滞，停止DNA合成以响应损伤和协调修复反应。已经开发出缺乏这些基因的小鼠模型。基因组重排如缺失与致癌作用有关。我们以前已经表明，X射线，苯并（a）芘（B（a）P）和顺铂引起DNA双链断裂，DNA加合物和DNA交联分别增加小鼠基因组中重复DNA序列之间的缺失频率。由于DNA复制，即p/un突变，导致p基因中断，导致毛色变淡，眼睛呈粉红色。这种复制在胚胎中回复为野生型，导致皮毛上的黑点和眼睛中的视网膜色素上皮。我们先前已经证明p53参与X射线，但不参与B（a）P诱导的p/un逆转。此外，X射线而非B（a）P以不依赖于p53的方式起作用。X射线以ATM依赖性方式诱导p53，而顺铂以ATM非依赖性方式诱导p53。这些致癌物将用于解剖小鼠胚胎中ATM/p53/p21/Gadd 45 DNA损伤的识别和修复。这些数据将与这些基因产物在胚胎中致癌诱导的诱导谱相关。也有人提出，氧化应激在AT的发病机制中起作用。我们建议确定氧化应激是否参与ATM小鼠对电离辐射的任何不同反应，我们将确定营养因素如促氧化剂和抗氧化剂是否对氧化应激参数有任何影响。如果ATM缺陷小鼠的缺失频率可以通过暴露于抗氧化剂来降低，这可能表明氧化应激可能至少部分地导致致癌的高发生率，这反过来可能会提高营养抗氧化剂干预的可能性。