The main strategy for bacteria to cope with metabolic stresses is through the stringent response triggered by the accumulation of the alarmone (p)ppGpp. While metazoan genomes also encode a homologue of the (p)ppGpp hydrolase SpoT (MESH1), neither a homologue of the (p)ppGpp synthetase nor (p)ppGpp itself has been found in metazoa. Therefore, the stringent response was thought to be absent in metazoa. Unexpectedly, we found that the silencing of MESH1 in mammalian cells triggered a cellular response highly similar to the bacterial stringent response. Such a response is characterized by the short-term stress survival, reversible proliferation arrest as well as extensive transcriptional and metabolic reprogramming. As (p)ppGpp is not found in metazoa, we hypothesize that Mesh1 mediates the novel cellular response by mechanisms independent of (p)ppGpp. In this proposal, we will investigate the biochemistry of the novel enzymatic activities of MESH1 and establish their functional contributions to the mammalian cells’ response to various stresses and stimuli. The successful execution of the proposed studies will help elucidate how the novel enzymatic activities of MESH1—the mammalian orthologue of the bacterial (p)ppGpp hydrolase—contribute to its biological function in mediating the mammalian cellular response to various stresses and stimuli and realize its therapeutic potential in human diseases.