Ocampo Maria T A, Chaung Wenren, Marenstein Dina R, Chan Michael K, Altamirano Alvin, Basu Ashis K, Boorstein Robert J, Cunningham Richard P, Teebor George W
Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016, USA.
Mol Cell Biol. 2002 Sep;22(17):6111-21. doi: 10.1128/MCB.22.17.6111-6121.2002.
DNA N-glycosylase/AP (apurinic/apyrimidinic) lyase enzymes of the endonuclease III family (nth in Escherichia coli and Nth1 in mammalian organisms) initiate DNA base excision repair of oxidized ring saturated pyrimidine residues. We generated a null mouse (mNth1(-/-)) by gene targeting. After almost 2 years, such mice exhibited no overt abnormalities. Tissues of mNth1(-/-) mice contained an enzymatic activity which cleaved DNA at sites of oxidized thymine residues (thymine glycol [Tg]). The activity was greater when Tg was paired with G than with A. This is in contrast to Nth1, which is more active against Tg:A pairs than Tg:G pairs. We suggest that there is a back-up mammalian repair activity which attacks Tg:G pairs with much greater efficiency than Tg:A pairs. The significance of this activity may relate to repair of oxidized 5-methyl cytosine residues (5meCyt). It was shown previously (S. Zuo, R. J. Boorstein, and G. W. Teebor, Nucleic Acids Res. 23:3239-3243, 1995) that both ionizing radiation and chemical oxidation yielded Tg from 5meCyt residues in DNA. Thus, this previously undescribed, and hence novel, back-up enzyme activity may function to repair oxidized 5meCyt residues in DNA while also being sufficient to compensate for the loss of Nth1 in the mutant mice, thereby explaining the noninformative phenotype.
核酸内切酶III家族的DNA N-糖基化酶/AP（无嘌呤/无嘧啶）裂解酶（大肠杆菌中的nth和哺乳动物中的Nth1）启动氧化的环饱和嘧啶残基的DNA碱基切除修复。我们通过基因靶向产生了一种基因敲除小鼠（mNth1(-/-)）。近2年后，这些小鼠未表现出明显异常。mNth1(-/-)小鼠的组织含有一种酶活性，该活性在氧化胸腺嘧啶残基（胸腺嘧啶乙二醇 [Tg]）位点切割DNA。当Tg与G配对时的活性比与A配对时更高。这与Nth1相反，Nth1对Tg:A对的活性比对Tg:G对更高。我们认为存在一种备用的哺乳动物修复活性，其对Tg:G对的攻击效率远高于Tg:A对。这种活性的意义可能与氧化的5-甲基胞嘧啶残基（5meCyt）的修复有关。先前的研究表明（S. Zuo、R. J. Boorstein和G. W. Teebor，《核酸研究》23:3239 - 3243，1995），电离辐射和化学氧化都会使DNA中的5meCyt残基产生Tg。因此，这种先前未描述的、因而新颖的备用酶活性可能在修复DNA中氧化的5meCyt残基的同时，也足以补偿突变小鼠中Nth1的缺失，从而解释了无信息表型。
