MOLECULAR PATHOLOGY OF CARCINOGENIC DNA DAMAGE

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The enzymic initiation of repair of photoalkylated bases in DNA will be investigated. An endonuclease activity that breaks such DNA will be purified from human placenta, cultured human cells and from Micrococcus luteus. These enzymes will be characterized. Detailed physical and chemical analysis of the substrate will be done to determine the precise type of DNA deformity recognized by the enzyme. The endonucleases will be assayed by measuring conversion of damaged superhelical DNA to the nicked form. The activity in normal cells will be compared to that in xeroderma pigmentosum, ataxia telangectasia and Fanconi's anemia, genetically transmitted diseases with high incidences of cancer. Deficiencies will be explored by standard biochemical techniques, including enzyme purification. Photoalkylation of DNA results in additions of alkyl groups at the 8-carbon of purines, an alteration shared with some chemical carcinogens. The effects of ultraviolet - induced pyrimidine dimers on excision of uracil from the DNA of cultured human cells will be investigated. Unrepaired damage in DNA is mutagenic and carcinogenic. Therefore these results will elucidate the mechanisms of excision-repair of DNA damage in normal cells and the defective mechanisms of human diseases that lead to the development of cancer.