Nicolaides N C, Littman S J, Modrich P, Kinzler K W, Vogelstein B
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Mol Cell Biol. 1998 Mar;18(3):1635-41. doi: 10.1128/MCB.18.3.1635.
Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a "two-hit" inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.
错配修复（MMR）基因缺陷通过诱导微卫星不稳定性（MI）导致突变表型，这是遗传性非息肉病性结直肠癌（HNPCC）以及一部分散发性结肠肿瘤的特征。目前描述MMR基因种系突变使家族易患HNPCC的机制的模型表明，特定MMR基因的两个等位基因会发生“两次打击”失活。在此，我们提供实验证据表明，hPMS2基因第134位密码子处的无义突变足以降低含有野生型hPMS2等位基因的细胞中的错配修复并诱导微卫星不稳定性。这些结果对于理解诱变与致癌作用之间的关系以及产生具有突变表型的哺乳动物细胞的能力具有重要意义。
