A mechanistic model of Rtc-regulated RNA repair suggests molecular targets to potentiate antibiotic effects

Abstract

AbstractRNA is susceptible to damage from various internal and external factors. Given the integral role of RNA, its repair is essential for maintaining proper cell function. A highly conserved RNA repair system, the Rtc system, maintains core RNA components of the translational apparatus. Rtc expression is induced upon various stresses, including exposure to ribosome-targeting antibiotics. Its expression enables cells to rescue growth and survive treatment by conferring transient resistance to these antibiotics. The mechanisms by which Rtc-induced resistance arises are largely unknown. Here, we develop and analyse a computational model of Rtc-regulated maintenance of long-lived RNAs that form part of the translational apparatus. We investigate the mechanistic action of Rtc leading to transient resistance and find that its regulatory structure promotes heterogeneity across bacterial populations, where a resistant sub-population can co-exist with non-expressing, susceptible cells. The finding suggests a complex response underlying adaptive resistance conferred by Rtc with individual cell fates determining antibiotic efficacy. We further analyse the molecular determinants that lead to growth rescue vs suppression and identify components within the Rtc system that may be targeted to potentiate antibiotic effects. Our results provide novel tools for the systems analysis of Rtc-regulated RNA repair and pinpoint testable hypotheses to advance knowledge of RNA repair and its physiological implications.