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.
| Original language | English |
|---|---|
| Pages (from-to) | 450-463 |
| Number of pages | 14 |
| Journal | Cancer Cell |
| Volume | 23 |
| Issue number | 4 |
| DOIs | |
| State | Published - 15 Apr 2013 |
Bibliographical note
Funding Information:We thank Roderick T. Bronson for analyzing tumors, Moon Hee Yang for help with allograft assays, Annie Lee for technical assistance, and the Nikon Imaging Center at Harvard Medical School. We thank Kevin Haigis for critical reading of the manuscript. S.M.J. was supported in part by a National Research Foundation of Korea grant funded by the Korean Government (NRF-2010-357-C00087). M.C.H. is supported in part by NIH grant AG032375, the Glenn Foundation for Medical Research, and the American Cancer Society New Scholar Award. A.K. is supported by the National Cancer Institute grant R01 CA157490, the Kimmel Scholar Award, and an AACR-PanCAN Career Development Award. This work was also supported in part by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.
