Sirt6 Promotes DNA End Joining in iPSCs Derived from Old Mice

Publication date: 21 March 2017
Source:Cell Reports, Volume 18, Issue 12
Author(s): Wen Chen, Nana Liu, Hongxia Zhang, Haiping Zhang, Jing Qiao, Wenwen Jia, Songcheng Zhu, Zhiyong Mao, Jiuhong Kang
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.

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Teaser

Chen et al. find that iPSCs from old mice show lower genomic stability and less efficient NHEJ repair than iPSCs from young mice. This decrease is rescued by overexpression of Sirt6 during reprogramming. Sirt6 binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus leading to efficient NHEJ.


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