Processing of Complex Lesions in the Mammalian Genome

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The mechanisms by which complex lesions particularly interstrand cross-links (ICLs) are removed or repaired in mammalian cells are poorly understood despite the importance of compounds that induce these lesions to human health. These compounds which are present in foodstuffs and produced as byproducts of mammalian metabolism, are highly toxic and mutagenic. Conversely, some of these drugs are also employed as highly active anti-tumor agents. The long term objectives of this application are a highly focused effort, involving four projects and three cores, to elucidate the molecular mechanisms of repair of ICLs with the anticipation that the knowledge gained from these studies will be of significant value to an understanding of both the etiology of tumorigenesis and the enhancement of chemotherapeutic regimens. This proposed dissection of the mechanisms of ICL repair will encompass both mutagenic and non-mutagenic pathways, as well as the complete process of repair from lesion recognition to the final stages of restoration of helical integrity. Both biochemical and genetic approaches will be employed to ascertain the molecular details of the multiple pathways of ICL repair. In addition, another objective of this application is to explore potential uses of ICL inducing compounds as a methodology to enhance recombination and mutagenesis in mammalian ceils. Specifically, the use of triplex technology will be employed to direct ICLs to a particular genetic target. If successful, these approaches could yield significant technical and therapeutic advances in genetic manipulation.