SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism.
SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism.
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DOI：
10.1016/j.ccr.2013.02.024
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发表时间：
2013-04-15
期刊：
影响因子：
50.3
通讯作者：
Haigis MC
中科院分区：
文献类型：
--
作者：
Jeong SM;Xiao C;Finley LW;Lahusen T;Souza AL;Pierce K;Li YH;Wang X;Laurent G;German NJ;Xu X;Li C;Wang RH;Lee J;Csibi A;Cerione R;Blenis J;Clish CB;Kimmelman A;Deng CX;Haigis MC
DNA损伤引发细胞信号传导反应，启动细胞周期停滞和DNA修复。在这里，我们发现DNA损伤触发了谷氨酰胺代谢的关键阻断，这是适当的DNA损伤反应所必需的。这种阻断需要线粒体SIRT4，其由许多遗传毒性剂诱导并抑制谷氨酰胺代谢进入TCA循环。SIRT4缺失导致谷氨酰胺依赖性增殖增加和应激诱导的基因组不稳定性，导致肿瘤发生表型。此外，SIRT4敲除小鼠自发地发展肺肿瘤。我们的数据揭示了SIRT4作为DNA损伤反应途径的重要组成部分，其协调谷氨酰胺代谢，细胞周期阻滞和肿瘤抑制中的代谢阻断。
DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into TCA cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest and tumor suppression.
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影响因子：
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