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首页> 外文期刊>Cell Reports >Homologous Recombination DNA Repair Genes Play a Critical Role in Reprogramming to a Pluripotent State
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Homologous Recombination DNA Repair Genes Play a Critical Role in Reprogramming to a Pluripotent State

机译：同源重组DNA修复基因在重编程为多能状态中起关键作用

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SummaryInduced pluripotent stem cells (iPSCs) hold great promise for personalized regenerative medicine. However, recent studies show that iPSC lines carry genetic abnormalities, suggesting that reprogramming may be mutagenic. Here, we show that the ectopic expression of reprogramming factors increases the level of phosphorylated histone H2AX, one of the earliest cellular responses to DNA double-strand breaks (DSBs). Additional mechanistic studies uncover a direct role of the homologous recombination (HR) pathway, a pathway essential for error-free repair of DNA DSBs, in reprogramming. This role is independent of the use of integrative or nonintegrative methods in introducing reprogramming factors, despite the latter being considered a safer approach that circumvents genetic modifications. Finally, deletion of the tumor suppressor p53 rescues the reprogramming phenotype in HR-deficient cells primarily through the restoration of reprogramming-dependent defects in cell proliferation and apoptosis. These mechanistic insights have important implications for the design of safer approaches to creating iPSCs.Graphical AbstractFigure optionsView in workspaceDownload full-size imageDownload as PowerPoint slideHighlights? Reprogramming increases the level of γH2AX, a marker of DNA DSBs ? Homologous recombination (HR) deficiency impairs reprogramming ? Reprogramming-induced DSBs and HR phenotypes are method-independent ? p53 deletion rescues reprogramming defects in HR-deficient cells.
机译：总结诱导型多能干细胞（iPSC）对于个性化再生医学具有广阔的前景。但是，最近的研究表明，iPSC系携带遗传异常，这表明重编程可能是诱变的。在这里，我们显示异位表达的重编程因子增加了磷酸化组蛋白H2AX的水平，这是对DNA双链断裂（DSBs）最早的细胞反应之一。其他机制研究揭示了在重组过程中同源重组（HR）途径（对DNA DSB进行无错误修复所必需的途径）的直接作用。此作用独立于在引入重编程因子中使用整合或非整合方法，尽管后者被认为是绕过基因修饰的更安全方法。最后，删除肿瘤抑制因子p53主要是通过恢复细胞增殖和凋亡中依赖重编程的缺陷来挽救HR缺陷细胞中的重编程表型。这些机制的见解对于设计创建iPSC的更安全方法具有重要意义。图形AbstractFigure选项在工作区中查看下载全尺寸图像下载为PowerPoint幻灯片突出显示吗？重新编程可增加DNA DSB的标记γH2AX的水平？同源重组（HR）缺陷会影响重编程吗？重编程诱导的DSB和HR表型与方法无关吗？ p53缺失可挽救HR缺陷细胞中的重编程缺陷。

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