Positional effects on the structure and stability of abbreviated H-ras DNA sequences containing O6-methylguanine residues at codon 12.
Positional effects on the structure and stability of abbreviated H-ras DNA sequences containing O6-methylguanine residues at codon 12.
复制标题
位置对密码子 12 处含有 O6-甲基鸟嘌呤残基的缩写 H-ras DNA 序列的结构和稳定性的影响。
DOI：
10.1021/tx00024a009
复制
发表时间：
1991
影响因子：
4.1
通讯作者：
Moschel,RC
中科院分区：
文献类型：
--
作者：
Bishop,RE;Moschel,RC
大鼠中 H-ras 原癌基因通过甲基化致癌物而被激活，这是由密码子 12 (GGA) 第二个位置处的 G 至 A 转变突变引起的，可能是由于在该位置处形成了 C^-甲基鸟嘌呤 (m6G)。密码子 12 第一个位置的类似转变似乎在体内不会发生。为了研究这种突变偏差的可能结构基础，我们合成了一系列 11 碱基的 H-ras 序列 [例如，5/-d (CGCTG* G* AGGCG)-3/和两条互补链]，在密码子 12 的第一个、第二个或两个位置上包含 m6G（即 G*= m6G）。溶液化学研究结果表明，单条链形成稳定的发夹结构，其中密码子12第二位含有m6G的发夹结构最稳定。此外，第二位置具有m6G的DNA双链体明显比第一位置具有m6G的DNA双链体更稳定，并且在某些条件下，它也比未修饰的双链体更稳定。这种稳定性差异可能会导致修复蛋白更容易地识别第一个位置的 m6G，并且这可能有助于通过甲基化 H-ras 基因密码子 12 处的致癌物而产生明显的位点特异性。
Activation of the H-ras protooncogene in rats by methylating carcinogens results from a G-to-A transition mutation at the second positionof codon 12 (GGA), presumably due to formation of an C^-methylguanine (m6G) at this position. A similar transition at the first position of codon 12 appears not to occur in vivo. To study the possible structural basis for this bias in mutation, we synthesized a series of 11-base H-ras sequences [eg, 5/-d (CGCTG* G* AGGCG)-3/and two complementary strands] containing an m6G at the first, second, or both positions of codon 12 (ie, G*= m6G). The results of solution chemical studies indicated that the individual strands formed stable hairpin structures among which that containing m6G at the second positionof codon 12 was most stable. Further, the DNA duplex with m6G at the second position was significantly more stable than that with m6G at the first position, and under certain conditions, it was more stable than the unmodified duplex as well. It is possible that such a difference in stability might lead to more ready recognition of an m6G at the first position by repair proteins, and this could contribute to the apparent site specificity of mutation by methylating carcinogens at codon 12 of the H-ras gene.