Sirt6 Promotes DNA End Joining in iPSCs Derived from Old Mice
Sirt6 Promotes DNA End Joining in iPSCs Derived from Old Mice
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Sirt6 促进老年小鼠 iPSC 中 DNA 末端的连接。
DOI：
10.1016/j.celrep.2017.02.082
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发表时间：
2017-03-21
期刊：
影响因子：
8.8
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
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作者：
Chen, Wen;Liu, Nana;Kang, Jiuhong
诱导多能干细胞(IPSCs)在治疗年龄相关疾病方面具有巨大潜力，但IPSCs的基因组完整性至关重要。在这里，我们证明了非同源末端连接(NHEJ)，而不是同源重组(HR)，在老年小鼠的IPSCs中的效率低于年轻小鼠。我们进一步发现，SIRT6在老年小鼠的IPSCs中下调。SIRT6直接与Ku80结合，促进Ku80/DNA-PKcs相互作用，从而促进S2056位DNA-PKcs的磷酸化，从而形成高效的NHEJ。救援实验表明，在重编程过程中引入SIRT6和Yamanaka因子的组合，通过激活NHEJ显著促进老年小鼠iPSCs的DNA双链断裂(DSB)修复。因此，我们的研究提出了一种策略，通过激活NHEJ和稳定基因组来提高来自老年捐赠者的IPSCs的质量。
Induced pluripotent stem cells (iPSCs) have great potential for treating age-related diseases, but the genome integrity of iPSCs is critically important. Here, we demonstrate that non-homologous end joining (NHEJ), rather than homologous recombination (HR), is less efficient in iPSCs from old mice than young mice. We further find that Sirt6 is downregulated in iPSCs from old mice. Sirt6 directly binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus promoting DNA-PKcs phosphorylation at residue S2056, leading to efficient NHEJ. Rescue experiments show that introducing a combination of Sirt6 and the Yamanaka factors during reprogramming significantly promotes DNA double-strand break (DSB) repair by activating NHEJ in iPSCs derived from old mice. Thus, our study suggests a strategy to improve the quality of iPSCs derived from old donors by activating NHEJ and stabilizing the genome.