Pfeifer Gerd P, You Young-Hyun, Besaratinia Ahmad
Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Mutat Res. 2005 Apr 1;571(1-2):19-31. doi: 10.1016/j.mrfmmm.2004.06.057. Epub 2005 Jan 20.
The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA bases. We also discuss the role of DNA damage-tolerant DNA polymerases in UV lesion bypass and mutagenesis.
不同的紫外线（UV）波长成分，即UVA（320 - 400纳米）、UVB（280 - 320纳米）和UVC（200 - 280纳米），具有不同的诱变特性。UVC和UVB诱变的一个标志是在含有胞嘧啶的二嘧啶序列处转换突变的频率很高。在人类皮肤癌中，p53基因中所有突变的约35%是在5'-TCG和5'-CCG序列内二嘧啶处的转换，并且这些突变位于几个突变热点。由于在人类细胞中5'-CG序列沿p53编码序列被甲基化，这些突变可能源自于在含有5-甲基胞嘧啶的序列处形成的阳光诱导的嘧啶二聚体。当细胞受到UVB或阳光照射时，环丁烷嘧啶二聚体（CPD）优先在含有5-甲基胞嘧啶的二嘧啶处形成。为了确定5-甲基胞嘧啶对阳光诱导突变的贡献，小鼠成纤维细胞中的lacI和cII转基因被用作诱变靶点。在254纳米UVC照射后，只有6 - 9%的碱基替换发生在含有5-甲基胞嘧啶的二嘧啶处。然而，24 - 32%的阳光诱导突变发生在含有5-甲基胞嘧啶的二嘧啶处，并且这些突变大多是转换。因此，优先在含有5-甲基胞嘧啶的二嘧啶处形成的CPD是哺乳动物细胞中阳光诱导突变的相当一部分原因。使用携带光产物特异性光解酶和诱变报告基因的小鼠细胞系，我们表明CPD（而非6 - 4光产物或其他损伤）是UVB诱导突变的绝大多数原因。UVB诱变的一个重要成分是CPD内胞嘧啶和5-甲基胞嘧啶的脱氨基作用。长波UVA（340 - 400纳米）的诱变特异性与较短波长的紫外线不同，其主要特征是G到T的颠换，可能是通过涉及氧化DNA碱基的机制产生的。我们还讨论了DNA损伤耐受DNA聚合酶在UV损伤绕过和诱变中的作用。
