Human cells contain singular DNA repair pathways to excise critical lesions from DNA. In individuals with clinical syndromes predisposing to malignancy, the capacity to excise these lesions is impaired. This research proposal is designed to continue our investigations on: 1) the biochemical and molecular mechanisms through which normal human cells regulate excision repair pathways during cell proliferation; and 2) whether aberrations in regulatory mechanisms of DNA repair may provide a molecular mechanism for the cellular sensitivities of individuals who may be cancer prone. In particular, in this research proposal, we plan to continue our examination of structural alterations in DNA repair enzymes from hypermutable cells from cancer prone individuals. For these studies, we shall use a series of monoclonal antibodies developed in this laboratory to the human placental uracil DNA glycosylase. The objectives of this proposal are: 1) To examine the immunological relationships and amino acid sequence homologies of normal human uracil DNA glycosylases. Through ELISA analysis using a series of three antihuman uracil DNA glycosylase monoclonal antibodies we shall determine the structure of each monoclonal antibody binding site as well as the catalytic and pyrimidine analogue binding sites. 2) To directly demonstrate the specificity and molecular basis for the altered antigenicity of the Bloom's syndrome uracil DNA glycosylase. We shall examine the structural basis for the altered antigenicity of the glycosylase isolated from five separate Bloom's syndrome patients as well as determining kinetic alterations of the Bloom's syndrome enzymes.
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