Elevated mutant frequencies and increased C:G→T:A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells
Elevated mutant frequencies and increased C:G→T:A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells
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DOI：
10.1038/sj.onc.1204138
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发表时间：
2001-02-01
期刊：
影响因子：
8
通讯作者：
Jirik, FR
中科院分区：
文献类型：
--
作者：
Baross-Francis, A;Makhani, N;Jirik, FR
DNA错配修复（MMR）基因突变与基因组不稳定性增加和癌症易感性相关。由于基因靶向而导致Mlh 1或Pms 2缺陷的小鼠易于发生肿瘤，特别是淋巴瘤。此外，尽管Mlh 1（-/-）小鼠也发生小肠腺瘤和腺癌，但Pms 2（-/-）动物仍然没有这种肿瘤。为了确定这种表型二分法是否可能与这些小鼠中基因组不稳定性的定量和/或定性差异有关，我们使用转基因λ-噬菌体lacI报告基因测定了小肠上皮细胞DNA突变频率和突变。从Mlh 1（-/-）和Pms 2（-/-）小鼠获得的突变频率分别显示了18和13倍的升高，与它们的野生型同窝仔相比。有趣的是，我们发现在MlH 1（/-）小鼠中C：G-->T：A转换显著升高，这在很大程度上解释了在这些动物中观察到的1.5倍lacI突变频率的增加。我们假设C：G-->T：A突变水平的增加可以部分解释为什么MlH 1（-/）小鼠而不是Pms 2（-/-）小鼠发生小肠肿瘤。此外，MlH 1和Pms 2（-/-）小鼠lacI突变谱的差异表明其他MutL样异源二聚体可能在小鼠小肠上皮细胞内产生的G：T错配修复中起重要作用。
Mutations in DNA mismatch repair (MMR) genes are associated with increased genomic instability and susceptibility to cancer. Mice rendered deficient in either Mlh1 or Pms2 as a result of gene targeting are prone to tumorigenesis, particularly, lymphomas, In addition, although Mlh1(-/-) mice also develop small intestinal adenomas and adenocarcinomas, Pms2(-/-) animals remain free of such tumors. To establish whether this phenotypic dichotomy might he associated with quantitative and/or qualitative difference in genomic instability in these mice, we determined small intestinal epithelial cell DNA mutant frequency and mutation using a transgenic lambda -phage lacI reporter Mutant frequencies obtained from both Mlh1(-/-) and Pms2(-/-) mice revealed elevations of 18 and 13-fold, respectively, as compared to their wild-type littermates. interestingly, we found that C:G-->T:A transitions, were significantly elevated in MlH1 (/-) mice, accounting in large measure for the 1.5-fold lacI mutant frequency increase seen in these animals, We hypothesize that the increased level of C:G-->T:A mutations may explain, in part, why Mlh1(-/) mice, but not Pms2(-/-) mice, develop small intestinal tumors, Furthermore, the difference in the lacI mutational spectrum of Mlh1 and Pms2(-/-) mice suggests that other MutL-like heterodimers may play important roles in the repair of G : T mispairs arising within murine small intestinal epithelial cells.