Samson L, Han S, Marquis J C, Rasmussen L J
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA 02115, USA.
Carcinogenesis. 1997 May;18(5):919-24. doi: 10.1093/carcin/18.5.919.
O6-Methylguanine (O6MeG) and O4-methylthymine (O4MeT) are potentially mutagenic DNA lesions that cause G:C-->A:T and A:T-->G:C transition mutations by mispairing during DNA replication, and the repair of O6MeG and O4MeT by DNA repair methyltransferases (MTases) is therefore expected to prevent methylation-induced transitions. The efficiency of O6MeG and O4MeT repair by different MTases can vary by several hundred-fold and the aim of this study was to establish the biological consequences of such differences in the efficiency of repair. The ability of three microbial and two mammalian MTases to prevent methylation-induced G:C-->A:T and A:T-->G:C transitions is taken as a measure of their ability to repair O6MeG and O4MeT in vivo respectively. All five MTases give complete protection against G:C-->A:T transitions. However, while the microbial MTases give complete protection against A:T-->G:C transitions, the mammalian MTases actually sensitize cells to A:T-->G:C transitions. We hypothesize that the mammalian MTases bind O4MeT lesions in vivo but that, because they are extremely slow at subsequent methyl transfer, binding shields O4MeT from repair by the nucleotide excision repair pathway. Results are presented to support this hypothesis.
O6-甲基鸟嘌呤（O6MeG）和O4-甲基胸腺嘧啶（O4MeT）是具有潜在诱变作用的DNA损伤，它们在DNA复制过程中通过错配导致G:C→A:T和A:T→G:C转换突变，因此，DNA修复甲基转移酶（MTases）对O6MeG和O4MeT的修复有望防止甲基化诱导的转换。不同MTases对O6MeG和O4MeT的修复效率可能相差数百倍，本研究的目的是确定这种修复效率差异的生物学后果。三种微生物MTases和两种哺乳动物MTases防止甲基化诱导的G:C→A:T和A:T→G:C转换的能力分别被视为它们在体内修复O6MeG和O4MeT的能力指标。所有五种MTases都能完全防止G:C→A:T转换。然而，虽然微生物MTases能完全防止A:T→G:C转换，但哺乳动物MTases实际上使细胞对A:T→G:C转换敏感。我们假设哺乳动物MTases在体内与O4MeT损伤结合，但由于它们在随后的甲基转移过程中极其缓慢，结合会使O4MeT免受核苷酸切除修复途径的修复。本文给出了支持这一假设的结果。
