Rasmussen L J, Samson L
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA 02115, USA.
Carcinogenesis. 1996 Sep;17(9):2085-8. doi: 10.1093/carcin/17.9.2085.
DNA mismatch repair defects in certain cell types confer resistance to the cytotoxic effects of alkylating agents, suggesting that a normally functioning DNA mismatch repair pathway can actually mediate alkylation-induced cell death. In eukaryotic cells this phenomenon is only observed in cells lacking adequate DNA methyltransferase for the repair of O6-methylguanine (O6MeG) DNA lesions. It has been proposed that O6MeG may act as a substrate for DNA mismatch repair when paired with cytosine and when mispaired with thymine and that repeated futile DNA mismatch repair at O6MeG DNA lesions is cytotoxic. Here we show that the Escherichia coli MutS DNA mismatch repair binding protein does indeed bind specifically to O6MeG DNA lesions. In contrast, MutS does not bind DNA containing another O-alkylated base, namely O4-methylthymine, or another kind of modified guanine, namely 8-oxoguanine. These results provide direct biochemical evidence for the involvement of DNA mismatch repair in specifically processing O6MeG DNA lesions.
某些细胞类型中的DNA错配修复缺陷赋予了对烷化剂细胞毒性作用的抗性，这表明正常运作的DNA错配修复途径实际上可以介导烷化诱导的细胞死亡。在真核细胞中，这种现象仅在缺乏足够的DNA甲基转移酶来修复O6-甲基鸟嘌呤（O6MeG）DNA损伤的细胞中观察到。有人提出，当O6MeG与胞嘧啶配对以及与胸腺嘧啶错配时，它可能作为DNA错配修复的底物，并且在O6MeG DNA损伤处反复进行无效的DNA错配修复具有细胞毒性。在这里，我们表明大肠杆菌MutS DNA错配修复结合蛋白确实特异性地结合O6MeG DNA损伤。相比之下，MutS不结合含有另一种O-烷基化碱基即O4-甲基胸腺嘧啶的DNA，也不结合另一种修饰的鸟嘌呤即8-氧鸟嘌呤。这些结果为DNA错配修复参与特异性处理O6MeG DNA损伤提供了直接的生化证据。
