MOLECULAR PATHOLOGY OF CARCINOGENIC DNA DAMAGE

DNA中光烷基化碱基修复的酶促起始将是 研究了 破坏这种DNA的内切核酸酶活性将是 从人胎盘、培养的人细胞和微球菌中纯化 黄体。 将对这些酶进行表征。 详细的物理和 将进行衬底的化学分析以确定 一种被酶识别的DNA畸形类型。 核酸内切酶将是 通过测量受损的超螺旋DNA向有切口的DNA的转化来测定。 form. 将正常细胞中的活性与干皮病中的活性进行比较 色素性共济失调、毛细血管扩张性共济失调和范可尼贫血，遗传性 传染疾病和癌症的高发率。 缺陷将被 通过标准的生化技术，包括酶 洁净. DNA的光烷基化导致烷基的加成 在嘌呤的8-碳上，与一些化学物质共享的改变 致癌物质。 紫外光诱导的嘧啶二聚体对 将尿嘧啶从培养的人细胞的DNA中切除， 研究了 DNA中未修复的损伤具有致突变性和致癌性。 因此，这些结果将阐明切除修复的机制， 正常细胞的DNA损伤与人类疾病的缺陷机制 导致癌症的发展。

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.