Specific Aims: The goal of this work is to obtain a clearer understanding of how DNA damage inflicted by environmental carcinogens is translated into biological effects such as cell death, mutation and neoplastic transformation. Objectives include: 1. Characterization of the chemical nature and sequence specificity of lesions created by selected agents. 2. The elucidation and interaction of defined DNA lesions with purified enzymes active in replication and repair of DNA. Two representative DNA damaging agents will be used: ultraviolet light and benzo(a)-pyrene.
Specific aims i nclude: 1. Determination of the structure of the PyC lesion and a newly discovered lesion that occurs at AA sequences. 2. Elucidation of the rapir pathways of the PyC lesion. 3. Investigation of events that transpire when DNA polymerases and polymerase complexes such as pol III* and mammalian replitase encounter UV and benzo(a) pyrene induced DNA damage sites. Although the work proposed here is focused on these specific environmental agents, the approaches developed can and will be applied to other environmental carcinogens as seems appropriate.
