Claij Nanna, Te Riele Hein
Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Oncogene. 2002 Apr 25;21(18):2873-9. doi: 10.1038/sj.onc.1205395.
Loss of DNA mismatch repair has been found in tumors associated with the familial cancer predisposition syndrome HNPCC (hereditary non-polyposis colorectal cancer) and a subset of sporadic cancers. MSH2 deficiency abolishes the action of the mismatch repair system, resulting in a phenotype which is characterized by an increased accumulation of base substitutions and frameshifts, enhanced recombination between homologous but non-identical DNA sequences, and tolerance to the cytotoxic effects of methylating agents. In this study we describe an embryonic stem cell line in which the level of MSH2 protein is 10-fold reduced compared to that in wild-type cells. Remarkably, these MSH2-low cells were as resistant to killing by methylating agents as cells completely lacking MSH2, while they had retained almost maximal mismatch repair capacity as judged from their anti-mutagenic and anti-recombinogenic capacity and the absence of microsatellite instability. In contrast, MSH2-low cells were highly sensitive to methylation-damage induced mutagenesis. Thus, 10-fold reduced MSH2 protein levels render cells resistant to the toxic and highly sensitive to the mutagenic effects of methylating agents. This condition is not manifested by microsatellite instability and may have implications for both the etiology and treatment of cancer.
在与家族性癌症易感性综合征HNPCC（遗传性非息肉病性结直肠癌）相关的肿瘤以及一部分散发性癌症中，已发现存在DNA错配修复功能缺失的情况。MSH2缺陷会使错配修复系统的功能丧失，从而导致一种表型，其特征为碱基替换和移码突变的积累增加、同源但非相同DNA序列之间的重组增强以及对甲基化剂细胞毒性作用的耐受性增强。在本研究中，我们描述了一种胚胎干细胞系，其中MSH2蛋白水平相较于野生型细胞降低了10倍。值得注意的是，这些MSH2低表达细胞对甲基化剂杀伤的抗性与完全缺乏MSH2的细胞一样，而从它们的抗诱变和抗重组能力以及微卫星不稳定性的缺失情况判断，它们几乎保留了最大的错配修复能力。相比之下，MSH2低表达细胞对甲基化损伤诱导的诱变高度敏感。因此，MSH2蛋白水平降低10倍会使细胞对甲基化剂的毒性产生抗性，但对其诱变作用高度敏感。这种情况未表现为微卫星不稳定性，可能对癌症的病因学和治疗都有影响。
