Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Stem Cell Reports. 2015 May 12;4(5):886-98. doi: 10.1016/j.stemcr.2015.04.004. Epub 2015 Apr 30.
Pluripotent stem cells must strictly maintain genomic integrity to prevent transmission of mutations. In human induced pluripotent stem cells (iPSCs), we found that genome surveillance is achieved via two ways, namely, a hypersensitivity to apoptosis and a very low accumulation of DNA lesions. The low apoptosis threshold was mediated by constitutive p53 expression and a marked upregulation of proapoptotic p53 target genes of the BCL-2 family, ensuring the efficient iPSC removal upon genotoxic insults. Intriguingly, despite the elevated apoptosis sensitivity, both mitochondrial and nuclear DNA lesions induced by genotoxins were less frequent in iPSCs compared to fibroblasts. Gene profiling identified that mRNA expression of several antioxidant proteins was considerably upregulated in iPSCs. Knockdown of glutathione peroxidase-2 and depletion of glutathione impaired protection against DNA lesions. Thus, iPSCs ensure genomic integrity through enhanced apoptosis induction and increased antioxidant defense, contributing to protection against DNA damage.
多能干细胞必须严格保持基因组完整性，以防止突变的传播。在人类诱导多能干细胞（iPSC）中，我们发现基因组监测是通过两种方式实现的，即对细胞凋亡的高度敏感和 DNA 损伤的极低积累。低凋亡阈值是由组成性 p53 表达和 BCL-2 家族的促凋亡 p53 靶基因的显著上调介导的，确保在受到遗传毒性损伤时能够有效地去除 iPSC。有趣的是，尽管细胞凋亡敏感性增加，但与成纤维细胞相比，iPSC 中由遗传毒物诱导的线粒体和核 DNA 损伤较少。基因谱分析确定，几种抗氧化蛋白的 mRNA 表达在 iPSC 中显著上调。谷胱甘肽过氧化物酶-2 的敲低和谷胱甘肽的耗竭会损害对 DNA 损伤的保护作用。因此，iPSC 通过增强细胞凋亡诱导和增加抗氧化防御来确保基因组完整性，从而有助于防止 DNA 损伤。
