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Cancer Cell DOI:10.1016/j.ccr.2013.02.024

SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism.

Publication TypeJournal Article
Year of Publication2013
AuthorsJeong, SMin, Xiao, C, Finley, LWS, Lahusen, T, Souza, AL, Pierce, K, Li, Y-H, Wang, X, Laurent, G, German, NJ, Xu, X, Li, C, Wang, R-H, Lee, J, Csibi, A, Cerione, R, Blenis, J, Clish, CB, Kimmelman, A, Deng, C-X, Haigis, MC
JournalCancer Cell
Date Published2013 Apr 15
KeywordsAnimals, Cell Growth Processes, Cell Line, Tumor, DNA Damage, DNA Repair, Female, Glutamine, HEK293 Cells, Hep G2 Cells, Humans, Male, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Neoplasms, Experimental, Signal Transduction, Sirtuins, Tumor Suppressor Proteins

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 tricarboxylic acid 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.


Alternate JournalCancer Cell
PubMed ID23562301
PubMed Central IDPMC3650305
Grant ListR01 AG032375 / AG / NIA NIH HHS / United States
R01 CA157490 / CA / NCI NIH HHS / United States
AG032375 / AG / NIA NIH HHS / United States
/ / Intramural NIH HHS / United States