ATM, P53, GADD45 AND P21 EFFECTS ON RECOMBINATION

DNA损伤如双链断裂（DSBs）、DNA加合物和DNA链交联会导致癌症。这种损伤可能导致细胞周期停滞，如果可以修复，则会启动修复反应，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损伤存在的信号，p53激活p21和Gadd45的转录，它们参与细胞周期阻滞，停止DNA合成以响应损伤并协调修复反应。缺乏这些基因的小鼠模型已经被开发出来。基因组重排如缺失与致癌有关。我们之前已经证明，x射线、苯并(a)芘（B(a)P）和顺铂引起DNA dsb， DNA加合物和DNA交联分别增加了小鼠基因组中重复DNA序列之间缺失的频率。DNA复制破坏p基因，即p/un突变，导致毛色被稀释，眼睛呈粉红色。这种复制在胚胎中向野生型的逆转导致皮毛上的黑点和眼睛中的视网膜色素上皮。我们之前的研究表明，p53参与x射线，但不参与B(a)P诱导的P /un逆转。此外，x射线而不是B(a)P以p53独立的方式起作用。x射线诱导p53依赖于ATM，而顺铂诱导p53不依赖于ATM。这些致癌物将用于解剖小鼠胚胎中ATM/p53/p21/Gadd45 DNA损伤的识别和修复。这些数据将与胚胎癌变诱导的这些基因产物的诱导谱相关联。也有人提出氧化应激在AT的发病机制中起作用。我们打算确定氧化应激是否参与了ATM小鼠对电离辐射的任何不同反应，我们将确定营养因子如促氧化剂和抗氧化剂是否对这些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而降低，这可能表明氧化应激可能至少部分地导致高致癌率，这反过来又可能提高营养抗氧化剂干预的可能性。

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.