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Classic Spotlight: Studies of the Stringent Response Richard L. Gourse,a Sean Crossonb Department of Bacteriology, University of Wisconsin—Madison, Madison, Wisconsin, USAa; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USAb


arly investigators of bacterial metabolism felt that the major activities of the cell must be balanced so that every component of the cell could be duplicated in the same time interval. They also realized that some systems were independent of one another: for example, carbohydrate metabolism could proceed even when growth was stopped by lack of nitrogen. With this mindset in the early 1950s, Sands and Roberts found that a reduction in amino acid availability resulted in a severe decline in stable “pentose nucleic acid” synthesis (1), i.e., rRNA and tRNA transcription is coupled to protein synthesis. We now know that starvation of bacterial cells for amino acids results in a stress response, called the stringent response, involving hundreds of genes. Although this term was initially used with reference to amino acid limitation, the conditions that induce the stringent response and the mechanisms involved differ in different branches of the bacterial domain. However, the term generally refers to changes in cell physiology resulting from increases in production of the signaling molecule (p)ppGpp. Many of the early papers that were instrumental in defining this stress response were published in the Journal of Bacteriology (JB). The identification of relA mutations, mutations that “relax” the strict dependence of RNA synthesis on translation, was critical to our understanding of the stringent response. The original isolation of a relA mutant by Borek and colleagues (2) was reported in JB, and relA mutations were subsequently mapped to a single chromosomal locus by Stent and Brenner (3). A large collection of relA mutants was identified in a JB paper by Fiil and Friesen (4) using a penicillin enrichment following amino acid deprivation that took advantage of the delay in cell growth (and thus in cell wall synthesis) that results from the relA mutant’s inability to adjust to changing nutritional conditions.


Cashel and Gallant then showed that relA encodes the major synthase responsible for synthesizing (p)ppGpp (5). (p)ppGpp interacts directly with RNA polymerase in proteobacteria, thereby globally reprogramming transcription. Later work identified other (p)ppGpp targets and linked (p)ppGpp to antibiotic tolerance and the bacterial persistence phenomenon (6, 7). These subjects and others continue to keep (p)ppGpp well represented in the pages of JB. REFERENCES 1. Sands MK, Roberts RB. 1952. The effects of a tryptophan-histidine deficiency in a mutant of Escherichia coli. J Bacteriol 63:505–511. 2. Borek EK, Rockenbach J, Ryan A. 1956. Studies on a mutant of Escherichia coli with unbalanced ribonucleic acid synthesis. J Bacteriol 71:318 –323. 3. Stent GS, Brenner S. 1961. A genetic locus for the regulation of ribonucleic acid synthesis. Proc Natl Acad Sci U S A 47:2005–2014. 4. Fiil N, Friesen JD. 1968. Isolation of “relaxed” mutants of Escherichia coli. J Bacteriol 95:729 –731. 5. Cashel M, Gallant J. 1969. Two compounds implicated in the function of the RC gene of Escherichia coli. Nature 221:838 – 841. 6. Rao NN, Liu S, Kornberg A. 1998. Inorganic polyphosphate in Escherichia coli: the phosphate regulon and the stringent response. J Bacteriol 180: 2186 –2193. 7. Rodionov DG, Ishiguro EE. 1995. Direct correlation between overproduction of guanosine 3=,5=-bispyrophosphate (ppGpp) and penicillin tolerance in Escherichia coli. J Bacteriol 177:4224 – 4229.

Citation Gourse RL, Crosson S. 2016. Classic spotlight: studies of the stringent response. J Bacteriol 198:1710. doi:10.1128/JB.00230-16. Address correspondence to Richard L. Gourse, [email protected] Copyright © 2016, American Society for Microbiology. All Rights Reserved. The views expressed in this Editorial do not necessarily reflect the views of the journal or of ASM.

Journal of Bacteriology

June 2016 Volume 198 Number 12

Classic Spotlight: Studies of the Stringent Response.

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