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Novel activities of human uracil DNA N-glycosylase for cytosine-derived products of oxidative DNA damage.

机译:人尿嘧啶DNA N-糖基化酶对胞嘧啶衍生的氧化性DNA损伤产物的新活性。

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摘要

Uracil DNA N-glycosylase is a repair enzyme that releases uracil from DNA. A major function of this enzyme is presumably to protect the genome from pre-mutagenic uracil resulting from deamination of cytosine in DNA. Here, we report that human uracil DNA N-glycosylase also recognizes three uracil derivatives that are generated as major products of cytosine in DNA by hydroxyl radical attack or other oxidative processes. DNA substrates were prepared by gamma-irradiation of DNA in aerated aqueous solution and incubated with human uracil DNA N-glycosylase, heat-inactivated enzyme or buffer. Ethanol-precipitated DNA and supernatant fractions were then separated. Supernatant fractions after derivatization, and pellets after hydrolysis and derivatization were analyzed by gas chromatography/isotope-dilution mass spectrometry. The results demonstrated that human uracil DNA N-glycosylase excised isodialuric acid, 5-hydroxyuracil and alloxan from DNA with apparent K(m) values of approximately 530, 450 and 660 nM, respectively. The excision of these uracil analogues is consistent with the recently described mechanism for recognition of uracil by human uracil DNA N-glycosylase [Mol,C.D., Arval,A.S., Slupphaug,G., Kavil,B., Alseth,I., Krokan,H.E. and Tainer,J.A. (1995) Cell, 80, 869-878]. Nine other pyrimidine- and purine-derived products that were identified in DNA samples were not substrates for the enzyme. The results indicate that human uracil DNA N-glycosylase may have a function in the repair of oxidative DNA damage.
机译:尿嘧啶DNA N-糖基化酶是一种修复酶,可从DNA释放尿嘧啶。据推测,这种酶的主要功能是保护基因组免受DNA胞嘧啶脱氨导致的致突变前的尿嘧啶。在这里,我们报道人类尿嘧啶DNA N-糖基化酶还识别出三种尿嘧啶衍生物,它们是通过羟基自由基攻击或其他氧化过程作为DNA中胞嘧啶的主要产物而生成的。通过在充气水溶液中对DNA进行伽玛射线辐照来制备DNA底物,并与人尿嘧啶DNA N-糖基化酶,热灭活的酶或缓冲液一起孵育。然后分离乙醇沉淀的DNA和上清液级分。通过气相色谱/同位素稀释质谱法分析衍生化后的上清级分以及水解和衍生化后的沉淀。结果表明,人尿嘧啶DNA N-糖基化酶从DNA中清除了异二聚尿酸,5-羟基尿嘧啶和四氧嘧啶,其表观K(m)值分别约为530、450和660 nM。这些尿嘧啶类似物的切除与最近描述的人尿嘧啶DNA N-糖基化酶识别尿嘧啶的机制[Mol,CD,Arval,AS,Slupphaug,G.,Kavil,B.,Alseth,I.,Krokan,他和泰纳(J.A.) (1995)Cell,80,869-878]。在DNA样品中鉴定出的其他9种嘧啶和嘌呤衍生产品不是该酶的底物。结果表明,人尿嘧啶DNA N-糖基化酶可能在氧化性DNA损伤的修复中具有功能。

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