Effect of parkin on DNA damage induced rearrangements

描述（由申请人提供）：帕金森病（PD）患者的总体癌症发病率和吸烟引起的癌症发病率明显降低。这种降低的癌症频率在早期发病的PD患者中更为明显，更可能是由于遗传易感性。人们对其潜在的生物学机制一无所知。帕金森氏突变使人易患帕金森病。已经产生了帕金基因突变的小鼠，它们表现出与PD患者相似的行为缺陷。这个应用是为了确定环境致癌因素对遗传不稳定性频率的影响是否可以在缺乏parkin的小鼠中降低。我们之前已经表明，体内的DNA缺失事件会因环境和遗传癌症易感因素而增加。缺失分析是基于皮毛和眼睛上黑点的定量分析，这些黑点是由双关突变的逆转引起的。这种逆转发生在p基因内部70kb重复序列的两个拷贝之间的重组导致一个拷贝的缺失。初步结果表明，包括苯并(a)芘、苯和香烟烟雾在内的多种致癌物可诱导小鼠DNA缺失。我们假设在缺乏parkin的小鼠中，环境致癌物诱导的DNA缺失可能会减少。此外，我们建议测定香烟烟雾引起的尼古丁和可替宁、DNA加合物、氧化DNA损伤、谷胱甘肽和抗氧化维生素的水平，以将这些水平与烟雾引起的DNA缺失水平联系起来，并可能获得帕金对此可能产生的任何影响的分子见解。如果我们的假设被证明是正确的，人们可以使用这些小鼠作为模型系统来进一步研究缺乏parkin与DNA修复和癌症相互作用的机制基础。

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.