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Hypermutation in Derepressed Operons of Escherichia Coli K12 (Stringent Response͞transcription͞mutations)

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Hypermutation in Derepressed Operons of Escherichia Coli K12 (Stringent Response͞transcription͞mutations) Proc. Natl. Acad. Sci. USA Vol. 96, pp. 5089–5094, April 1999 Evolution Hypermutation in derepressed operons of Escherichia coli K12 (stringent responseytranscriptionymutations) BARBARA E. WRIGHT*, ANGELIKA LONGACRE, AND JACQUELINE M. REIMERS Division of Biological Sciences, University of Montana, Missoula, MT 59812 Communicated by E. R. Stadtman, National Heart, Lung and Blood Institute, Bethesda, MD, February 16, 1999 (received for review December 15, 1998) ABSTRACT This article presents evidence that starva- the concentration of single-stranded DNA (ssDNA), which is tion for leucine in an Escherichia coli auxotroph triggers more vulnerable to mutations than double-stranded DNA. metabolic activities that specifically target the leu operon for Although the mutations per se are random, as described above derepression, increased rates of transcription, and mutation. for background mutations, the mechanisms that target oper- Derepression of the leu operon was a prerequisite for its ons for increased rates of transcription are highly specific. This activation by the signal nucleotide, guanosine tetraphosphate, specificity is not compatible with current neo-Darwinian which accumulates in response to nutritional stress (the dogma. And yet, evidence in the literature supports the two stringent response). A quantitative correlation was estab- major assumptions on which our hypothesis is based: (i) lished between leuB mRNA abundance and leuB2 reversion ssDNA is more vulnerable to mutagenesis than double- rates. To further demonstrate that derepression increased stranded DNA; increased rates of transcription will, therefore, mutation rates, the chromosomal leu operon was placed under increase rates of mutation; and (ii) derepression and activation the control of the inducible tac promoter. When the leu operon of an amino acid biosynthetic operon occur specifically in was induced by isopropyl-D-thiogalactoside, both leuB mRNA response to starvation for that amino acid. abundance and leuB2 reversion rates increased. These inves- Evolution implies stress; a perfectly adapted organism in a tigations suggest that guanosine tetraphosphate may contrib- stable environment would not need to evolve. In fact, evidence ute as much as attenuation in regulating leu operon expression from marine fossil communities indicates that environmental and that higher rates of mutation are specifically associated stress accelerates the rate of evolution (7). In microorganisms, with the derepressed leu operon. prolonged nutritional stress results in genome-wide hypermu- tation, i.e., high mutation rates in various genes located in The mechanisms of evolution have been the subject of many chromosomes, episomes, transposons, or insertion elements controversies and speculations for some 200 years (1, 2). (8–14). Such effects likely contribute to the evolutionary Clearly, selection of the fittest occurs, but does the environ- process by increasing the size of the mutant population. ment also play a role in generating the fittest? Do all of the Indeed, hypermutable genes apparently have been selected variants selected result from mutations that are completely during evolution as uniquely advantageous to the survival of ‘‘random’’? Background mutations are loosely referred to as the organism (15). The question then arises: By what mecha- random even though they do not occur with equal probability, nism(s) related to stress could specific genes become hyper- but at different and characteristic rates because of DNA mutable? Transcription-enhanced hypermutation is a plausi- context and variables such as the intrinsic instability of cyto- ble mechanism by which a direct causal relationship can be sine, giving rise to the (most frequent) C-to-T transition established between higher mutation rates in specific genes mutations (3, 4) or the presence of tandem repeats, resulting and the selective conditions of stress that evoke them. There in frameshift mutations (5). Moreover, environmental condi- is an accepted biochemical basis for the stimulation of tran- tions such as thymidine starvation can selectively increase the scription by starvation (derepression); for example, the lack of an amino acid results in the derepression of the operon rate of particular kinds of mutation (6). However, in an controlling its synthesis. Because increased rates of transcrip- evolutionary context, ‘‘random’’ has a very specific meaning: tion can cause higher mutation rates in specific operons (see Neo-Darwinism holds that the spectrum of background mu- Discussion), a direct causal relationship appears to exist be- tations and the frequency with which they occur are random tween starvation for a particular amino acid and higher (undirected) with respect to selective conditions of the envi- mutation rates in genes of the operon encoding the enzymes ronment. Another ambiguous word, ‘‘mechanism,’’ can mean that catalyze its synthesis. one thing when applied to evolution and another when applied The metabolism of starvation is called the stringent response to mutations. There are mechanisms by which particular kinds (17). After deprivation of any essential nutrient, the cell of mutations occur (e.g., base substitution, deletion, frame- restructures its metabolism from one geared to growth and cell shift), and there are mechanisms by which the rates of many division under favorable nutritional conditions to one allowing kinds of background mutations are stimulated (e.g., replica- survival under conditions of starvation. This abrupt shift in tion, UV irradiation, defective repair, transcription). It is the metabolism results in the rapid accumulation (16, 17) of latter sort of mechanism that applies to evolution because guanosine tetraphosphate (ppGpp), a signal nucleotide that stimulating mutation rates increases the availability of variants appears to be the most dominant primary regulator of nutri- on which evolution depends. Our data indicate that transcrip- tional distress (17, 18). It is synthesized by ppGpp synthase I, tion (starvation-induced derepression) is unique in augment- the relA gene product, and is degraded by the spoT gene ing variant availability in a specific manner, i.e., by stimulating product. Recent investigations have demonstrated that this rates of transcription (and associated phenomena such as RNA signal nucleotide binds to the b-subunit of RNA polymerase polymerase pausing) in targeted operons, thereby increasing (19) and affects both transcription initiation (20) and poly- merase pausing (21). By recognizing particular promoter The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in Abbreviations: IPTG, isopropyl-D-thiogalactoside; ssDNA, single- accordance with 18 U.S.C. §1734 solely to indicate this fact. stranded DNA; ppGpp, guanosine tetraphosphate. PNAS is available online at www.pnas.org. *To whom reprint requests should be addressed. 5089 Downloaded by guest on October 3, 2021 5090 Evolution: Wright et al. Proc. Natl. Acad. Sci. USA 96 (1999) sequences (17, 22), ppGpp serves three essential roles for the RNA Probe Preparation. The E. coli leuB, pyrD, and glpK starving cells. The first two occur regardless of the starvation genes were PCR amplified and cloned into a vector containing regimen and consist of the inhibition of DNA, rRNA, nucle- opposable T3 and T7 promoter sites (pBluescript II SK(1), otide, and phospholipid synthesis, thereby arresting cell divi- Statagene). For each gene, plasmid DNA was isolated (Quan- sion and the activation of metabolic pathways that protect the tumPrep mini-prep kit, Bio-Rad) and cut with a restriction vulnerable cells from environmental extremes such as heat, enzyme to produce a 100- to 600-bp section of the gene with desiccation, and oxidative damage (17, 18). The third essential either the T3 or T7 promoter at one end. Antisense RNA role is starvation regimen-dependent in that ppGpp activates probes were produced by in vitro transcription (Ampliscribe T3 only those genes that are specifically derepressed by the type and T7 in vitro transcription kit, Epicentre Technologies, of starvation imposed. For example, the expression of amino Madison, WI). The probes were labeled with biotin (BrightStar acid biosynthetic operons requires both derepression (removal Psoralen-Biotin kit, Ambion) and were purified by using of end product inhibition by attenuation or repression) and denaturing polyacrylamide gel electrophoresis. The probes 9 activation by ppGpp. Starvation for tryptophan as well as other contained some vector sequence at the 5 end that was amino acids elicits the stringent response, but only tryptophan nonhomologous to the target mRNA, producing protected starvation increases trp expression (23); the absence of thre- hybrid fragments that were shorter than the full-length probe onine, but not arginine or histidine, leads to derepression of and separable by gel electrophoresis. This difference in pro- the thr operon (24). However, regulation in some operons tected vs. full length probe is evidence of a working assay. As apparently may be triggered as a general consequence of the a standard, positive-sense mRNA was generated for each gene stringent response (17). from the same plasmid but using the other promoter. Nuclease Protection Assay and Densitometry. The biotin- ylated antisense RNA probe of defined length was hybridized MATERIALS AND METHODS overnight to the target mRNA in solution at 50°C. After Bacterial Strains
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