Bacteria have evolved protective networks against diverse stresses such as nutrient starvation, temperature changes, osmotic shifts, and antibiotic stress. The small signaling molecules are important components of this protective network. Results from my lab suggest that small molecules, including the starvation-signaling nucleotide (p)ppGpp and nucleotides AppppA, ppApp, and c-di-AMP, induce rapid and coordinated changes in cellular metabolism. Failure of metabolic regulation by signaling nucleotides results in metabolic conflict and cellular toxicity. We are systematically characterizing signaling molecule-proteome interactions, pinpointing the molecular details of allosteric enzyme regulations underlying the metabolic network, and characterizing how the metabolic network enables homeostatic control principles and rapid adjustment of cellular coordination in diverse environments.
Coordination of macromolecular machines and genome evolution
A central component of bacterial stress response is coordination between macromolecular machineries. Bacteria accurately duplicate and process their genetic information using macromolecular machines including the replisome, the transcription complex, and the ribosome. The signaling nucleotide (p)ppGpp not only regulates metabolism but also directly regulates the DNA replication primase, transcription factors, and translation machineries, thus coordinating macromolecular machines. Importantly, we unraveled the detrimental consequences of failure to coordinate macromolecular machines: stress-induced physical conflicts between replication and transcription machineries that threaten genome integrity. Our current goals are to pinpoint the impact of conflicts on genome evolution, elucidate multifaceted coordination of machineries beyond replication and transcription, and characterize conflict-resolution pathways.