Rusmintratip V, Sowers L C
Divisions of Pediatrics and Molecular Medicine, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14183-7. doi: 10.1073/pnas.97.26.14183.
The oxidation of thymine in DNA can generate a base pair between 5-hydroxymethyluracil (HmU) and adenine, whereas the oxidation and deamination of 5-methylcytosine (5mC) in DNA can generate a base pair between HmU and guanine. Using synthetic oligonucleotides containing HmU at a defined site, HmU-DNA glycosylase activities in HeLa cell and human fibroblast cell extracts have been observed. An HmU-DNA glycosylase activity that removes HmU mispaired with guanine has been measured. Surprisingly, the HmU:G excision activity is 60 times greater than the corresponding HmU:A activity, even though the expected rate of formation of the HmU:A base pair exceeds that of the HmU:G base pair by a factor of 10(7). The HmU:G mispair would arise from the 5mC:G base pair, and, if unrepaired, would give rise to a transition mutation. The observation of an unexpectedly high HmU:G glycosylase activity suggests that human cells may encounter the HmU:G mispair much more frequently than expected. The conversion of 5mC to HmU must be considered as a potential pathway for the generation of 5mC to T transition mutations, which are often found in human tumors.
DNA中胸腺嘧啶的氧化可在5-羟甲基尿嘧啶（HmU）与腺嘌呤之间形成碱基对，而DNA中5-甲基胞嘧啶（5mC）的氧化和脱氨基作用可在HmU与鸟嘌呤之间形成碱基对。利用在特定位点含有HmU的合成寡核苷酸，已在HeLa细胞和人成纤维细胞提取物中观察到HmU-DNA糖基化酶活性。已测定了一种能去除与鸟嘌呤错配的HmU的HmU-DNA糖基化酶活性。令人惊讶的是，HmU:G切除活性比相应的HmU:A活性高60倍，尽管HmU:A碱基对的预期形成速率比HmU:G碱基对的形成速率高10^7倍。HmU:G错配将由5mC:G碱基对产生，并且如果不修复，将导致转换突变。对HmU:G糖基化酶活性意外高的观察表明，人类细胞可能比预期更频繁地遇到HmU:G错配。必须将5mC向HmU的转化视为产生5mC到T转换突变的潜在途径，这种突变在人类肿瘤中经常发现。
