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

Cancer Cell. 2013 Apr 15;23(4):450-63. doi: 10.1016/j.ccr.2013.02.024.

Seung Min Jeong ¹, Cuiying Xiao, Lydia W S Finley, Tyler Lahusen, Amanda L Souza, Kerry Pierce, Ying-Hua Li, Xiaoxu Wang, Gaëlle Laurent, Natalie J German, Xiaoling Xu, Cuiling Li, Rui-Hong Wang, Jaewon Lee, Alfredo Csibi, Richard Cerione, John Blenis, Clary B Clish, Alec Kimmelman, Chu-Xia Deng, Marcia C Haigis

Affiliations

Affiliation

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

PMID: 23562301 DOI: 10.1016/j.ccr.2013.02.024

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.