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.
Showing the most recent 10 out of 33 publications
