Influences of environmental agents on Alu/Alu recombination

Alu元件之间的不平等重组事件导致与癌症和出生缺陷相关的人类基因组不稳定性的显著部分。有超过50个独立的Alu/Alu重组事件导致不同的人类疾病的例子。先前的研究表明，各种诱变化合物有助于增加随机重复序列之间的重组率。这些分析表明，重组环境污染物往往有不同的影响小突变与重组。我们推测，诱变剂也将有助于分散的Alu元素之间的重组，虽然不同的诱变剂的刺激可能是不相同的这两种不同类型的重组。因此，我们已经设计了一个报告的系统，将被引入到组织培养细胞和转基因小鼠，允许直接测量Alu/Alu重组率。我们相信，该测定法将比以前的测定法更能代表人类基因组中发生的典型重组事件。Alu/Alu重组试验将用于检测暴露于广泛诱变剂后重组率的增加。将特别注意芳烃，因为它们代表了这样一种普遍存在且稳定的污染物。特别是，苯并[a]芘与。将进行各种卤代芳族烃以确定在更易代谢的烃与不可代谢的烃之间是否存在重组潜力的差异。此外，还将进行研究，以确定芳烃受体在任何重组刺激中的作用。

Unequal recombination events between Alu elements contribute to a significant portion of human genome instabilities associated with cancer and birth defects. There are over 50 independent examples of Alu/Alu recombination events causing different human diseases. Previous studies have shown that various mutagenic compounds contribute to increased recombination rates between randomly repeated sequences. These assays have demonstrated that recombination environmental pollutants often have different influences on small mutations versus recombination. We hypothesize that mutagens will also contribute to the more recombination between dispersed Alu elements, although the stimulation by different mutagens may not be identical between these two different types of recombinant. Thus, we have designed a reported system that will be introduced into tissue culture cells and transgenic mice to allow the direct measurement of Alu/Alu recombination rates. We believe that this assay will be more representative of typical recombination events occurring in the human genome than previous assays. The Alu/Alu recombination assay will be utilized to test for increases in recombination rate upon exposure to a broad range of mutagens. Particular attention will be paid to the aryl hydrocarbons because they represent such a ubiquitous and stable class of pollutants. In particular, studies of benzo[a]pyrene versus. various halogenated aromatic hydrocarbons will be carried out to determine whether there are differences in recombination potential between the more metabolizable hydrocarbons versus no-.metabolizable ones. In addition, studies to determine the role of the aryl hydrocarbon receptor in any recombination stimulation will be carried out.