Aird Katherine M, Worth Andrew J, Snyder Nathaniel W, Lee Joyce V, Sivanand Sharanya, Liu Qin, Blair Ian A, Wellen Kathryn E, Zhang Rugang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2015 May 12;11(6):893-901. doi: 10.1016/j.celrep.2015.04.014. Epub 2015 Apr 30.
Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence.
核苷酸缺乏诱导的复制应激在癌症发生中起重要作用。原代细胞中的复制应激通常会激活细胞衰老肿瘤抑制机制。衰老逃逸与癌症的发展相关，癌症是一种以代谢重编程为特征的疾病。然而，代谢重编程在细胞对复制应激反应中的作用鲜有研究。在此，我们报告共济失调毛细血管扩张症突变基因（ATM）通过改变细胞代谢在调节细胞对复制应激的反应中起核心作用。ATM失活绕过了由核苷酸缺乏引发的复制应激所诱导的衰老。这是由于通过增加葡萄糖-6-磷酸脱氢酶（G6PD）活性上调磷酸戊糖途径以及增强葡萄糖和谷氨酰胺消耗，使脱氧核糖核苷酸三磷酸（dNTP）水平得以恢复。这些表型是由ATM失活下游p53的协同抑制和c-MYC的上调介导的。我们的数据表明，在衰老过程中，ATM状态将复制应激与代谢重编程联系起来。
