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首页> 外文期刊>Journal of Molecular Biology >Acceleration of 5-methylcytosine deamination in cyclobutane dimers by G and its implications for UV-induced C-to-T mutation hotspots.
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Acceleration of 5-methylcytosine deamination in cyclobutane dimers by G and its implications for UV-induced C-to-T mutation hotspots.

机译：G对环丁烷二聚体中5-甲基胞嘧啶脱氨基的促进作用及其对UV诱导的C-T突变热点的影响。

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Sunlight-induced C-->T mutation hotspots occur most frequently at methylated CpG sites in tumor suppressor genes and are thought to arise from translesion synthesis past deaminated cyclobutane pyrimidine dimers (CPDs). While it is known that methylation enhances CPD formation in sunlight, little is known about the effect of methylation and sequence context on the deamination of 5-methylcytosine ((m)C) and its contribution to mutagenesis at these hotspots. Using an enzymatic method, we have determined the yields and deamination rates of C and (m)C in CPDs and find that the frequency of UVB-induced CPDs correlates with the oxidation potential of the flanking bases. We also found that the deamination of T(m)C and (m)CT CPDs is about 25-fold faster when flanked by G's than by A's, C's or T's in duplex DNA and appears to involve catalysis by the O6 group of guanine. In contrast, the first deamination of either C or (m)C in AC(m)CG with a flanking G was much slower (t(1/2) >250 h) and rate limiting, while the second deamination was much faster. The observation that C(m)CG dimers deaminate very slowly but at the same time correlate with C-->T mutation hotspots suggests that their repair must be slow enough to allow sufficient time for deamination. There are, however, a greater number of single C-->T mutations than CC-->TT mutations at C(m)CG sites even though the second deamination is very fast, which could reflect faster repair of doubly deaminated dimers.
机译：阳光诱导的C-> T突变热点最常出现在肿瘤抑制基因的甲基化CpG位点，并被认为是通过脱氨基的环丁烷嘧啶二聚体（CPD）的跨病变合成引起的。尽管已知甲基化会增强阳光下CPD的形成，但对于甲基化和序列背景对5-甲基胞嘧啶（（m）C）脱氨基及其对这些热点诱变的影响知之甚少。使用酶法，我们确定了CPD中C和（m）C的产率和脱氨率，并发现UVB诱导的CPD的频率与侧基的氧化电位相关。我们还发现，在双链体DNA中，T（m）C和（m）CT CPD的脱氨作用在G侧比A，C或T侧快约25倍，并且似乎涉及鸟嘌呤O6基团的催化作用。相反，在带有侧翼G的AC（m）CG中进行C或（m）C的第一次脱氨要慢得多（t（1/2）> 250 h）和速率限制，而第二次脱氨要快得多。 C（m）CG二聚体的脱氨基速度非常慢，但同时又与C-> T突变热点相关，这一观察表明，它们的修复必须足够慢才能有足够的时间进行脱氨。但是，尽管第二次脱氨非常快，但在C（m）CG位点，单C→T突变的数量比CC→TT突变的数量要多，这可能反映了双脱氨基二聚体的修复更快。

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