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

Cancer Cell
Authors
Keywords
Abstract

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.

Year of Publication
2013
Journal
Cancer Cell
Volume
23
Issue
4
Pages
450-63
Date Published
2013 Apr 15
ISSN
1878-3686
DOI
10.1016/j.ccr.2013.02.024
PubMed ID
23562301
PubMed Central ID
PMC3650305
Links
Grant list
R01 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