p53 isoform Δ133p53 promotes efficiency of induced pluripotent stem cells and ensures genomic integrity during reprogramming.
p53 isoform Δ133p53 promotes efficiency of induced pluripotent stem cells and ensures genomic integrity during reprogramming.
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p53 亚型 Delta 133p53 可提高诱导多能干细胞的效率并确保重编程期间基因组的完整性
DOI：
10.1038/srep37281
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发表时间：
2016-11-22
影响因子：
4.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Gong L;Pan X;Chen H;Rao L;Zeng Y;Hang H;Peng J;Xiao L;Chen J
人类诱导多能干细胞（iPS）在再生医学中具有巨大的潜力，但这取决于其基因组的完整性。已经发现iPS细胞由于重编程期间的DNA损伤反应而含有大量从头遗传改变。因此，维持iPS细胞的遗传稳定性是iPS细胞技术的重要目标。DNA损伤反应可以触发肿瘤抑制基因p53的激活，从而通过诱导细胞凋亡和衰老来确保重编程细胞的基因组完整性。p53亚型Δ133p53是p53的靶基因，其功能不仅是拮抗p53介导的凋亡，而且促进DNA双链断裂（DSB）修复。在这里，我们报告了Δ133p53在重编程中被诱导。敲低Δ133p53导致重编程效率降低2倍，染色体畸变增加4倍，而与仅用4种Yamanaka因子诱导的iPS细胞相比，用4种Yamanaka因子过表达Δ133p53显示重编程效率增加4倍，染色体畸变减少2倍。过表达Δ133p53可抑制细胞凋亡，促进重编程过程中DNA DSB修复灶的形成。我们的发现表明Δ133p53的过表达不仅提高了iPS细胞的重编程效率，而且导致更好的遗传质量。
Human induced pluripotent stem (iPS) cells have great potential in regenerative medicine, but this depends on the integrity of their genomes. iPS cells have been found to contain a large number of de novo genetic alterations due to DNA damage response during reprogramming. Thus, to maintain the genetic stability of iPS cells is an important goal in iPS cell technology. DNA damage response can trigger tumor suppressor p53 activation, which ensures genome integrity of reprogramming cells by inducing apoptosis and senescence. p53 isoform Δ133p53 is a p53 target gene and functions to not only antagonize p53 mediated apoptosis, but also promote DNA double-strand break (DSB) repair. Here we report that Δ133p53 is induced in reprogramming. Knockdown of Δ133p53 results 2-fold decrease in reprogramming efficiency, 4-fold increase in chromosomal aberrations, whereas overexpression of Δ133p53 with 4 Yamanaka factors showes 4-fold increase in reprogamming efficiency and 2-fold decrease in chromosomal aberrations, compared to those in iPS cells induced only with 4 Yamanaka factors. Overexpression of Δ133p53 can inhibit cell apoptosis and promote DNA DSB repair foci formation during reprogramming. Our finding demonstrates that the overexpression of Δ133p53 not only enhances reprogramming efficiency, but also results better genetic quality in iPS cells.