Effect of parkin on DNA damage induced rearrangements

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DESCRIPTION (provided by applicant): The frequency of cancer overall and of cigarette smoke induced cancer specifically is reduced in Parkinson's Disease (PD) patients. This reduced cancer frequency is more pronounced among early onset PD patients that are more likely due to genetic predisposition. Nothing is known about the underlying biological mechanism. Mutations in parkin predispose people to PD. Mice with a knockout mutation in the parkin gene have been generated and they show behavioral deficits similar to PD patients. This application is to determine whether the effect on the frequency of genetic instability of environmental cancer causing factors can be reduced in mice lacking parkin. We have previously shown that DNA deletion events in vivo are increased by environmental as well as genetic cancer predisposing factors. The deletion assay is based on the quantification of black spots on fur and eyes resulting from reversion of the pun mutation. This reversion occurs by recombination between two copies of an internal 70 kb repeat within the p gene leading to deletion of one copy. In preliminary results we showed that a variety of carcinogens including benzo(a)pyrene, benzene and cigarette smoke induce DNA deletions in mice. We hypothesize for aim 1 that such induction of DNA deletions by environmental carcinogens may be reduced in mice lacking parkin. In addition, we propose to determine cigarette smoke induced levels of nicotine and cotinine, DNA adducts, oxidative DNA lesions, glutathione and antioxidant vitamins to correlate such levels with the levels of smoke induced DNA deletions and to possibly gain molecular insights into any possible effect of parkin thereon. If our hypothesis turns out to be true, one could use these mice as model systems to further study the mechanistic basis of the interaction of lack of parkin with DNA repair and cancer.