C→T mutagenesis and γ-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases
C→T mutagenesis and γ-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases
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DOI：
10.1038/sj.emboj.7600689
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发表时间：
2005-06-15
期刊：
影响因子：
11.4
通讯作者：
Barnes, DE
中科院分区：
文献类型：
--
作者：
An, Q;Robins, P;Barnes, DE
需氧生物中最常见的遗传变化是 C:G 到 T:A 突变。 C -> T 转变可以通过胞嘧啶自发水解脱氨基产生错误编码的尿嘧啶残基。这也是一种常见的 DNA 损伤，由氧化损伤、暴露于电离辐射等物质或与退行性疾病、衰老和癌症病因有关的内源性来源引起。 Ung 和 Smug1 酶从 DNA 中切除尿嘧啶以实现哺乳动物细胞的修复，并且基因靶向的 Ung(-/-) 小鼠表现出全基因组自发突变的适度增加。在这里，我们报道了小鼠胚胎成纤维细胞中 Smug1 的稳定 siRNA 介导的沉默也会产生突变表型。然而，在同时缺乏 Smug1 和 Ung 的细胞中，自发的 C:G 到 T:A 转变增加了 10 倍，这表明这些酶在抑制非 CpG 位点的 C -> T 突变性方面具有独特且非冗余的作用。这些细胞对电离辐射也高度敏感，并揭示了 Smug1 在修复胞嘧啶氧化产生的损伤中的作用。
The most common genetic change in aerobic organisms is a C:G to T:A mutation. C -> T transitions can arise through spontaneous hydrolytic deamination of cytosine to give a miscoding uracil residue. This is also a frequent DNA lesion induced by oxidative damage, through exposure to agents such as ionizing radiation, or from endogenous sources that are implicated in the aetiology of degenerative diseases, ageing and cancer. The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung(-/-) mice exhibit a moderate increase in genome-wide spontaneous mutagenesis. Here, we report that stable siRNA-mediated silencing of Smug1 in mouse embryo fibroblasts also generates a mutator phenotype. However, an additive 10-fold increase in spontaneous C:G to T:A transitions in cells deficient in both Smug1 and Ung demonstrates that these enzymes have distinct and nonredundant roles in suppressing C -> T mutability at non-CpG sites. Such cells are also hypersensitive to ionizing radiation, and reveal a role of Smug1 in the repair of lesions generated by oxidation of cytosine.