BIOCHEMICAL AND STRUCTURAL ANALYSIS OF THE SOS SIGNAL COMPLEX

Evolution is driven by the accumulation of genetic variation that undergoes environmental selection. While mostly thought of as a passive process, some organisms have adapted mechanisms to attenuate the rate of accumulation of genetic variation in response to environmental conditions, driving genetic diversity at the population level. Bacteria have become particularly adept at responding to environmental cues to maximize their likelihood of adaptation and survival, which has potentiated the growing global health crisis of antibiotic resistance. The key to combatting antibiotic-resistant microbes is a better understanding of the mechanisms that underlie bacterial adaptation that can inform strategies to counter these mechanisms. One such pathway of particular interest is the bacterial SOS response. The SOS response is a highly conserved genetic network that serves to sense and respond to DNA damage-inducing environmental stressors, such as UV irradiation. Activation of SOS is associated with both repair of damaged DNA in a high-fidelity manner, and paradoxically, transient hypermutation. Because many antibiotics act, either directly or indirectly, through disparate mechanisms to cause DNA damage, they also cause upregulation of the SOS response. For these reasons, inhibition of the SOS response is a potentially powerful novel therapeutic target. Rational design of potent inhibitors first necessitates a greater understanding of both the biochemical steps involved in SOS activation as well as a more detailed understanding of the structural composition and arrangement of the SOS signal complex itself.