Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building 101 College St., 15th Floor, Room 15-312 East Tower, Toronto, ON, M5G 1L7, Canada.
DNA Repair (Amst). 2013 Jan 1;12(1):46-52. doi: 10.1016/j.dnarep.2012.10.006. Epub 2012 Nov 24.
Mismatch repair (MMR) proteins have critical roles in the maintenance of genomic stability, both class-switch recombination and somatic hypermutation of immunoglobulin genes and disease-associated trinucleotide repeat expansions. In the genetic absence of MMR, certain tissues are predisposed to mutations and cancer. MMR proteins are involved in various functions including protection from replication-associated and non-mitotic mutations, as well as driving programmed and deleterious mutations, including disease-causing trinucleotide repeat expansions. Here we have assessed the levels of MSH2, MSH3, and MSH6 expression in a large number of murine tissues by transcript analysis and simultaneous Western blotting. We observed that MMR expression patterns varied widely between 14 different tissue types, but did not vary with age (13-84 weeks). MMR protein expression is highest in testis, thymus and spleen and lowest in pancreas, quadriceps and heart, with intermediate levels in liver, kidney, intestine, colon, cortex, striatum and cerebellum. By equalizing antibody signal intensity to represent levels found in mMutSα and mMutSβ purified proteins, we observed that mMSH3 protein levels are greater than mMSH6 levels in the multiple tissues analyzed, with more MSH6 in proliferating tissues. In the intestinal epithelium MSH3 and MSH6 are more highly expressed in the proliferative undifferentiated cells of the crypts than in the differentiated villi cells, as reported for MSH2. This finding correlates with the higher level of MMR expression in highly proliferative mouse tissues such as the spleen and thymus. The relative MMR protein expression levels may explain the functional and tissue-specific reliance upon the roles of each MMR protein.
错配修复（MMR）蛋白在维持基因组稳定性方面发挥着关键作用，包括免疫球蛋白基因的类别转换重组和体细胞高频突变以及与疾病相关的三核苷酸重复扩展。在 MMR 基因缺失的情况下，某些组织易发生突变和癌症。MMR 蛋白参与多种功能，包括防止复制相关和非有丝分裂突变，以及驱动程序性和有害突变，包括引起疾病的三核苷酸重复扩展。在这里，我们通过转录分析和同时进行的 Western blot 分析评估了大量鼠组织中 MSH2、MSH3 和 MSH6 的表达水平。我们观察到，MMR 表达模式在 14 种不同组织类型之间差异很大，但不随年龄（13-84 周）而变化。MMR 蛋白表达在睾丸、胸腺和脾脏中最高，在胰腺、四头肌和心脏中最低，在肝脏、肾脏、肠道、结肠、皮质、纹状体和小脑中有中等水平。通过将抗体信号强度等化以代表从 mMutSα 和 mMutSβ 纯化蛋白中发现的水平，我们观察到在分析的多种组织中 mMSH3 蛋白水平高于 mMSH6 水平，并且在增殖组织中有更多的 MSH6。在肠道上皮细胞中，MSH3 和 MSH6 在隐窝的增殖未分化细胞中的表达高于分化的绒毛细胞，这与 MSH2 的报道一致。这一发现与 MMR 表达水平较高的高度增殖的鼠组织（如脾脏和胸腺）相关。相对 MMR 蛋白表达水平可能解释了每种 MMR 蛋白在功能和组织特异性上的依赖性。
