Genomic instability and altered metabolism are key features of many cancer cells. Thus, defining pathways involved in regulating DNA damage responses and cellular metabolism hold important implications for understanding normal cell growth, as well as for the development of strategies to prevent or treat cancer. A recent paper from the Haigis Lab (Jeong et al, Cancer Cell, 2013) sheds new light on understanding of how cells adapt their metabolism in response to DNA damage. Jeong and colleagues report that a mitochondria-localized sirtuin, SIRT4, is up-regulated in response to DNA-damaging agents, and coordinates repression of mitochondrial glutamine metabolism with cell arrest. Loss of SIRT4 promotes genomic instability and tumor growth in mice. Moreover, SIRT4 expression is decreased in many human cancers. These findings suggest that SIRT4 has tumor suppressive activity, and provides a new link between glutamine metabolism and genomic integrity.