Na Hyun-Jin, Akan Ilhan, Abramowitz Lara K, Hanover John A
Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2020 May 12;31(6):107632. doi: 10.1016/j.celrep.2020.107632.
Stem/progenitor cells exhibit high proliferation rates, elevated nutrient uptake, altered metabolic flux, and stress-induced genome instability. O-GlcNAcylation is an essential post-translational modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which act in a nutrient- and stress-responsive manner. The precise role of O-GlcNAc in adult stem cells and the relationship between O-GlcNAc and the DNA damage response (DDR) is poorly understood. Here, we show that hyper-O-GlcNacylation leads to elevated insulin signaling, hyperproliferation, and DDR activation that mimic the glucose- and oxidative-stress-induced response. We discover a feedback mechanism involving key downstream effectors of DDR, ATM, ATR, and CHK1/2 that regulates OGT stability to promote O-GlcNAcylation and elevate DDR. This O-GlcNAc-dependent regulatory pathway is critical for maintaining gut homeostasis in Drosophila and the DDR in mouse embryonic stem cells (ESCs) and mouse embryonic fibroblasts (MEFs). Our findings reveal a conserved mechanistic link among O-GlcNAc cycling, stem cell self-renewal, and DDR with profound implications for stem-cell-derived diseases including cancer.
干细胞表现出高增殖率、营养物质摄取增加、代谢通量改变以及应激诱导的基因组不稳定。O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是一种由O-GlcNAc转移酶（OGT）和O-GlcNAcase（OGA）介导的重要翻译后修饰，它们以营养和应激反应的方式发挥作用。O-GlcNAc在成体干细胞中的精确作用以及O-GlcNAc与DNA损伤反应（DDR）之间的关系尚不清楚。在这里，我们表明高O-GlcNAcylation会导致胰岛素信号增强、过度增殖和DDR激活，这模拟了葡萄糖和氧化应激诱导的反应。我们发现了一种涉及DDR关键下游效应器ATM、ATR和CHK1/2的反馈机制，该机制调节OGT稳定性以促进O-GlcNAcylation并增强DDR。这种O-GlcNAc依赖性调节途径对于维持果蝇肠道内稳态以及小鼠胚胎干细胞（ESC）和小鼠胚胎成纤维细胞（MEF）中的DDR至关重要。我们的研究结果揭示了O-GlcNAc循环、干细胞自我更新和DDR之间保守的机制联系，对包括癌症在内的干细胞衍生疾病具有深远影响。
