Sirt6 Promotes DNA End Joining in iPSCs Derived from Old Mice.
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.
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Wen
W
Chen
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Nana
N
Liu
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Hongxia
H
Zhang
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Haiping
H
Zhang
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Jing
J
Qiao
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Wenwen
W
Jia
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China.
Songcheng
S
Zhu
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China. Electronic address: zhiyong_mao@tongji.edu.cn.
Zhiyong
Z
Mao
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China. Electronic address: jhkang@tongji.edu.cn.
Jiuhong
J
Kang
D000375:Aging / Q000378:metabolism*; D000818:Animals; D065150:Cellular Reprogramming; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D042822:Genomic Instability; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D000072200:Ku Autoantigen / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D037761:Sirtuins / Q000378:metabolism*; D012867:Skin / Q000166:cytology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010768:Phosphoserine; C501860:Sirt6 protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D037761:Sirtuins; D000072200:Ku Autoantigen
Ku80; NHEJ repair; SirT6