THE ROLE OF DNA BINDING IN MOUSE SKIN TUMOR INITIATION

人类不断地暴露在各种各样的化学物质中， 其中一些可能作为引发剂、促进剂、辅致癌物 和/或完全致癌物。 目前的证据表明， DNA的共价修饰在生物学中起着核心作用。 不同种类的致癌物质引发肿瘤的机制 包括多环芳烃（PAH）的试剂。 然而，仍有待确定哪些DNA加合物 最重要的是，DNA加合物是否被有效地去除， 在DNA中引入错误;或者DNA- 加合物必须在DNA中存在很长一段时间， 肿瘤起始。 这项研究旨在进一步 研究PAH DNA加合物的去除和持久性的作用 与小鼠皮肤肿瘤起始有关。 老鼠皮是一口井 PAH的已知靶组织，是一种广泛研究的模型系统 皮肤癌的原因 该建议的具体目标如下： 如下 的形成之间的定量关系 特定的烃DNA加合物（尤其是dAdo加合物）和 将确定皮肤肿瘤起始。 范围和时间 各种诱导的程序外DNA合成过程 将检查PAH。 我们亦会研究 去除特定的DNA加合物（尤其是dAdo加合物）， 与皮肤肿瘤引发潜能的关系。 此外，我们将 继续探索的形成，去除，和持久性 表皮亚群中的烃DNA加合物 与小鼠DNA加合物双相消失的关系 表皮 我们将进一步研究DNA复制的作用 在肿瘤开始时，通过测定定量的 特定加合物形成与抑制的关系 表皮DNA合成和通过DNA合成的使用 抑制剂的 最后，为了更好地了解生物学， 特定PAH DNA加合物的生物化学和分子效应， 我们将从抗BPDE制备位点定向的dAdo加合物， 整合到细菌载体中。 这种方法将使我们 为了验证特定的碳氢化合物DNA加合物 需要在皮肤肿瘤开始后早期应用。

Humans are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens and/or complete carcinogens. Current evidence suggests that covalent modification of DNA plays a central role in the mechanism of tumor initiation by diverse classes of carcinogenic agents including polycyclic aromatic hydrocarbons (PAH). However, it remains to be determined which DNA-adducts are most important; whether DNA-adducts are removed efficiently or inefficiently thus introducing errors in the DNA; or whether DNA- adducts must persist in the DNA for long periods of time for tumor initiation. The proposed research is designed to further investigate the role of PAH DNA-adduct removal and persistence in relation to skin tumor initiation in mice. Mouse skin is a well known target tissue for PAH and is a widely studied model system for skin carcinogenesis. The specific aims of the proposal are as follows. The quantitative relationship between the formation of specific hydrocarbon DNA-adducts (especially dAdo adducts) and skin tumor-initiation will be determined. The extent and time course of unscheduled DNA synthesis induced by a variety of PAHs will be examined. We will also examine the rates of removal of specific DNA-adducts (especially dAdo adducts) in relation to skin tumor-initiating potency. Furthermore, we will continue to explore the formation, removal, and persistence of hydrocarbon DNA-adducts in epidermal subpopulations in relation to the biphasic disappearance of DNA-adducts in mouse epidermis. We will further examine the role of DNA replication at the time of tumor initiation by determining the quantitative relationship between specific adduct formation and inhibition of epidermal DNA synthesis and through the use of DNA synthesis inhibitors. Finally, to learn more about the biological, biochemical and molecular effects of specific PAH DNA-adducts, we will prepare site directed dAdo adducts from anti BPDE to be incorporated into a bacterial vector. This approach will allow us to test the hypothesis that specific hydrocarbon DNA-adducts are required early after application for skin tumor initiation.