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

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.supported by the National Basic Research Program of China (973 Program),the Strategic Priority Research Program of the Chinese Academy of Sciences,the National High Technology Research and Development Program of China,the National Natural Science Foundation of China,Beijing Natural Science Foundation,Program of Beijing Municipal Science and Technology Commission,Key Research Program of the Chinese Academy of Sciences,the Thousand Young Talents Program of China, National Laboratory of Biomacro-molecules,State Key Laboratory of Drug Research,China Postdoctoral Science Foundation Grant,China Postdoctoral Science Foundation Funded project,supported by NIH,the V Scholar award, American Cancer Society seed grant, Breast Cancer Research Award and Oberley Award (National Cancer Institute Award,Holden Comprehensive Cancer Center at the University of Iowa, and startup funds from the Department of Pathology, University of IowaSCI(E)PubMed中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)ARTICLEqujing@ioz.ac.cn; tangfuchou@pku.edu.cn; ghliu@ibp.ac.cn2190-2052