SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2

Abstract

SIRT6 belongs to the mammalian homologs of Sir2 histone NAD(+)-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which was required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay.

DOI: 10.1038/cr.2016.4

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@inproceedings{Pan2016SIRT6SH, title={SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2}, author={Huize Pan and Di Guan and Xiaomeng Liu and Jingyi Li and Lixia Wang and Jun Wu and Junzhi Zhou and Weizhou Zhang and Ruotong Ren and Weiqi Zhang and Ying Li and Jiping Yang and Ying Hao and Tingting Yuan and Guohong Yuan and Hu Wang and Zhenyu Ju and Zhiyong Mao and Jian Li and Jing Qu and Fuchou Tang and Guang-Hui Liu}, booktitle={Cell research}, year={2016} }