Swann P F
Department of Biochemistry, University College and Middlesex School of Medicine, London, Great Britain.
Mutat Res. 1990 Nov-Dec;233(1-2):81-94. doi: 10.1016/0027-5107(90)90153-u.
The carcinogenic and mutagenic N-nitroso compounds produce GC to AT and TA to GC transition mutations because they alkylate O6 of guanine and O4 of thymine. It has been generally assumed that these mutations occur because O6-alkylguanine forms a stable mispair with thymine and O4-alkylthymine forms a mispair with guanine. Recent studies have shown that this view is mistaken and that the alkylG.T and alkylT.G mispairs are not more stable than their alkylG.C or alkylT.A counterparts. Two possible explanations based on recent structural studies are put forward to account for the miscoding. The first possibility is that the DNA polymerase might mistake O6-alkylguanine for adenine, and O4-alkylthymine for cytosine, because of the physical similarity of these bases. O6-Methylguanine and adenine are similarly lipophilic and X-ray crystallography of the nucleosides has shown a close similarity in bond angles and lengths between O6-methylguanine and adenine, and between O4-methylthymine and cytosine. The second possible explanation is that the important factor in the miscoding is that the alkylG.T and alkylT.G mispairs retain the Watson-Crick alignment with N1 of the purine juxtaposed to N3 of the pyrimidine while the alkylG.C and alkylT.A pairs adopt a wobble conformation. 31P NMR of DNA duplexes show that the phosphodiester links both 3' and 5' to the C have to be distorted to accommodate the O6-ethylguanine:C pair, whereas there is less distortion of the phosphodiesters 3' and 5' to the T in an ethylG.T pair. Recent kinetic measurements show that the essential aspect of base selection in DNA synthesis is the ease of formation of the phosphodiester links on both the 3' and 5' side of the incoming base. The Watson-Crick alignment of the alkylG.T and alkylT.G mispairs may facilitate formation of these phosphodiester links, and this alignment rather than the strength of the base pairs and the extent of hydrogen bonding between them may be the crucial factor in the miscoding. If either hypothesis is correct it suggests that previously too much emphasis has been placed on the stability of the normal pairs in the replication of DNA.
致癌和致突变的N-亚硝基化合物会导致GC到AT以及TA到GC的转换突变，因为它们会使鸟嘌呤的O6和胸腺嘧啶的O4烷基化。人们普遍认为这些突变的发生是因为O6-烷基鸟嘌呤与胸腺嘧啶形成稳定的错配，O4-烷基胸腺嘧啶与鸟嘌呤形成错配。最近的研究表明这种观点是错误的，并且烷基G.T和烷基T.G错配比它们的烷基G.C或烷基T.A对应物更不稳定。基于最近的结构研究提出了两种可能的解释来解释错义编码。第一种可能性是，由于这些碱基的物理相似性，DNA聚合酶可能会将O6-烷基鸟嘌呤误认为腺嘌呤，将O4-烷基胸腺嘧啶误认为胞嘧啶。O6-甲基鸟嘌呤和腺嘌呤具有相似的亲脂性，核苷的X射线晶体学显示O6-甲基鸟嘌呤与腺嘌呤之间以及O4-甲基胸腺嘧啶与胞嘧啶之间在键角和键长上有密切的相似性。第二种可能的解释是，错义编码中的重要因素是烷基G.T和烷基T.G错配保持了嘌呤的N1与嘧啶的N3并列的沃森-克里克排列，而烷基G.C和烷基T.A对则采用摆动构象。DNA双链体的31P NMR表明，为了容纳O6-乙基鸟嘌呤:C对，与C相连的3'和5'的磷酸二酯键都必须扭曲，而在乙基G.T对中，与T相连的3'和5'的磷酸二酯键的扭曲较小。最近的动力学测量表明，DNA合成中碱基选择的关键方面是在进入碱基的3'和5'侧形成磷酸二酯键的难易程度。烷基G.T和烷基T.G错配的沃森-克里克排列可能有助于这些磷酸二酯键的形成，并且这种排列而不是碱基对的强度以及它们之间的氢键程度可能是错义编码中的关键因素。如果任何一个假设是正确的，这表明在DNA复制中，以前对正常碱基对稳定性的强调过多了。
