Site- and strand-specific mismatch repair of human H-ras genomic DNA in a mammalian cell line
Site- and strand-specific mismatch repair of human H-ras genomic DNA in a mammalian cell line
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DOI：
10.1093/carcin/18.7.1311
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发表时间：
1997-07-01
期刊：
影响因子：
4.7
通讯作者：
Williams, KJ
中科院分区：
文献类型：
--
作者：
Arcangeli, L;Simonetti, J;Williams, KJ
有缺陷的错配修复最近被认为是来自遗传性非息肉病性结肠癌（HNPCC）患者的突变表型肿瘤细胞系的主要贡献者。来自其他癌症易感综合征的细胞系，如着色性干皮病，已被发现在受损碱基的核苷酸切除修复中有缺陷。一些遗传互补组在转录偶联切除修复中有缺陷，尽管这种类型的修复缺陷与癌症易感性无关。致癌基因激活点突变发生率高的机制除了上述DNA修复机制外，可能在这些位点上还存在新的错误修复或错误复制机制。在这项研究中，我们比较了四种错配的链定向错配修复率，（G：A、A：C、T：C和G：T）在H-ras密码子12处，中间G：我们的研究结果表明，虽然这个位置不是细菌错配修复的“热点”，但它是NIH 3 T3细胞内特定错配碱基修复减少的“热点”，NIH 3 T3，与大肠杆菌不同，NIH 3 T3在该位置的G：A错配（35%）和A：C错配（58%）的修复率极低，NIH 3 T3在密码子12位置的T：C错配（80%）的修复率也中等低，相反，NIH 3 T3的G：T（100%）的修复率与大肠杆菌相当。这些结果表明，在NIH 3 T3细胞中，在H-ras密码子12中间碱基对位置的任一链上含有不正确的腺嘌呤的错配最有可能经历突变事件，相反，在转录链中含有不正确的胸腺嘧啶的错配最不可能经历突变事件。
Defective mismatch repair has recently been implicated as the major contributor towards the mutator phenotype tumour cell lines derived from patients hereditary non-polyposis colon cancer (HNPCC). Cell lines from other cancer-prone syndromes, such as xeroderma pigmentosum, have been found to be defective in nucleotide excision repair of damaged bases, Some genetic complementation groups are defective specifically in transcription-coupled excision repair, although this type of repair defect has not been associated with cancer proneness. Mechanisms contributing to the high incidence of activating point mutations in oncogenes (such as H-ras codon 12) are not understood, It is possible that novel mechanisms of misrepair or misreplication occur at these sites in addition to the above DNA repair mechanisms, In this study, we have compared the rate of strand-directed mismatch repair of four mispairs (G:A, A:C, T:C and G:T) at the H-ras codon 12, middle G:C position, Our results indicate that, although this location is not a 'hot spot' for bacterial mismatch repair, it is a 'hot spot' for decreased repair of specific mismatched bases within NIH 3T3 cells, NIH 3T3, unlike Escherichia coli, have an extremely low repair rate of the G:A mispair (35%), as well as the A:C mispair (58%) at this location, NIH 3T3 also have a moderately low repair rate of the T:C mispair (80%) at the codon 12 location, Conversely, NIH 3T3 repair of G:T (100%) is comparable to E. coli repair (94%) of this mismatch, These results demonstrate that a mismatch containing an incorrect adenine on either strand at the H-ras codon 12 middle base pair location is most likely to undergo a mutational event in NIH 3T3 cells, Conversely, a mismatch containing an incorrect thymine in the transcribed strand is least likely to undergo a mutational event.