Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency
Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency
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DOI：
10.1038/s41467-019-13830-x
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发表时间：
2020-01-10
影响因子：
16.6
通讯作者：
Abe, Masumi
中科院分区：
文献类型：
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作者：
Araki, Ryoko;Hoki, Yuko;Abe, Masumi
已经在重编程的多能干细胞如iPSC和ntESC中鉴定了许多点突变。然而，这些突变的分子基础仍然难以捉摸，这对其潜在的医学应用是一个相当大的障碍。在这里，我们报告了一个特定的阶段，在这个阶段，iPSC的生成不会因电离辐射而减少，即辐射抗性。非常有趣的是，G1/S细胞周期检查点缺陷在基因组重编程过程的初始阶段以短暂的方式发生。这些癌症样现象，即导致点突变积累的细胞周期检查点缺陷，表明iPSC生成和肿瘤发生之间存在共同的发育途径。这一概念得到了这些细胞中特定癌症突变特征的鉴定的支持。我们描述了使用成红细胞有效生成人无整合iPSC，其仅具有少量点突变和INDEL，其中没有一个在编码区中。
A number of point mutations have been identified in reprogrammed pluripotent stem cells such as iPSCs and ntESCs. The molecular basis for these mutations has remained elusive however, which is a considerable impediment to their potential medical application. Here we report a specific stage at which iPSC generation is not reduced in response to ionizing radiation, i.e. radio-resistance. Quite intriguingly, a G1/S cell cycle checkpoint deficiency occurs in a transient fashion at the initial stage of the genome reprogramming process. These cancer-like phenomena, i.e. a cell cycle checkpoint deficiency resulting in the accumulation of point mutations, suggest a common developmental pathway between iPSC generation and tumorigenesis. This notion is supported by the identification of specific cancer mutational signatures in these cells. We describe efficient generation of human integration-free iPSCs using erythroblast cells, which have only a small number of point mutations and INDELs, none of which are in coding regions.