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Review
. 2007 Sep-Oct;42(5):399-435.
doi: 10.1080/10409230701648502.

Mutation as a stress response and the regulation of evolvability

Rodrigo S Galhardo  1 , P J Hastings, Susan M Rosenberg
Affiliations
Review

Mutation as a stress response and the regulation of evolvability

Rodrigo S Galhardo et al. Crit Rev Biochem Mol Biol. 2007 Sep-Oct.

Abstract

Our concept of a stable genome is evolving to one in which genomes are plastic and responsive to environmental changes. Growing evidence shows that a variety of environmental stresses induce genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating adaptive evolution. The emerging molecular mechanisms of stress-induced mutagenesis vary but share telling common components that underscore two common themes. The first is the regulation of mutagenesis in time by cellular stress responses, which promote random mutations specifically when cells are poorly adapted to their environments, i.e., when they are stressed. A second theme is the possible restriction of random mutagenesis in genomic space, achieved via coupling of mutation-generating machinery to local events such as DNA-break repair or transcription. Such localization may minimize accumulation of deleterious mutations in the genomes of rare fitter mutants, and promote local concerted evolution. Although mutagenesis induced by stresses other than direct damage to DNA was previously controversial, evidence for the existence of various stress-induced mutagenesis programs is now overwhelming and widespread. Such mechanisms probably fuel evolution of microbial pathogenesis and antibiotic-resistance, and tumor progression and chemotherapy resistance, all of which occur under stress, driven by mutations. The emerging commonalities in stress-induced-mutation mechanisms provide hope for new therapeutic interventions for all of these processes.

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Figures

FIGURE 1
FIGURE 1
Most E. coli natural isolates display stress-inducible mutagenesis. Bjedov et al. (2003) examined 787 natural isolates from various habitats for mutagenesis in aging colonies on solid medium, a starvation stress. The frequencies of rifampicin-resistant (base-substitution) mutants per viable cell after seven days in an aging colony relative to that after only one day are shown for all 787 strains. Numbers greater than one indicate induction of mutagenesis. More than 80% showed stress-inducible mutagenesis, indicating a common feature of many natural isolates. Figure re-drawn from Rosenberg and Hastings’s (2003) review of the Bjedov et al. paper.
FIGURE 2
FIGURE 2
The E. coli Lac assay for stress-induced mutagenesis. Above: schematic representation of the strain used in the Lac assay. This strain bears a ~200 kb F′ conjugative plasmid carrying the mutant lacIZ33 allele, a lacI-lacZ fusion gene with a +1 frameshift mutation. Below: generation-dependent mutation events occurring during growth of the culture prior to plating on lactose medium are detected as Lac+ colonies present on about day 2. During subsequent days of incubation, stress-induced Lac+ colonies accumulate, and include both Lac+ point mutants with a compensatory frameshift mutation or lac-amplified cells, with 20 to 50 copies of DNA spanning the lac gene, which provides sufficient beta-galactosidase activity for growth without a frameshift reversion mutation (Hastings et al., 2004).
FIGURE 3
FIGURE 3
A switch from high-fidelity to error-prone DNA double-strand-break repair underlies stress-induced mutagenesis in the Lac system. Double-strand breaks are repaired via high-fidelity HR-DSBR in cells growing in optimal conditions. However, in growth-limited cells expressing the RpoS stress-response regulon, DSBs are repaired mutagenically under the control of RpoS, which somehow licenses the use of the DinB error-prone polymerase, which is upregulated by the SOS and RpoS responses. Mismatch repair (MMR) becomes limiting under this condition, and fails to correct many DNA polymerase errors, we suggest due to saturation/titration of MutL protein by excess DNA polymerase errors (described in the text). Single lines represent strands of DNA except in the two circular molecules at the bottom, where they represent whole bacterial chromosomes composed of double-stranded DNA. X’s represent DNA polymerase errors, and then mutations in the bottom-most molecule.
FIGURE 4
FIGURE 4
The switch to mutagenic double-strand-break repair in stationary phase, or if RpoS is expressed. Data reprinted with permission from Ponder et al. (2005), on stress-induced mutagenesis in the E. coli Lac system. Here, reversion not of lac but of a tetA+1 frameshift allele near to lac is assayed in cells grown in medium without lactose (such that no DNA amplification is selected, reviewed in the text). (A) An I-SceI endonuclease-generated DSB made near tetA is induced at a low level continuously during exponential growth and then stationary phase (blue line represents growth curve), but provokes DinB-dependent tetA reversion (red lines) only in stationary phase. (B) Mutation rate data from a mid-logarithmic-phase time point from experiments as in A, but this time with the RpoS, general stress-response transcriptional activator protein produced weakly from a plasmid. DinB-dependent tetA reversion occurs during mid-log phase if RpoS is expressed and DSBs are induced, showing that stationary phase is not necessary if RpoS is supplied even at low levels.
FIGURE 5
FIGURE 5
Model for the origin of the hypermutable cell subpopulation in the Lac system: convergence of two stress responses. We suggest that the hypermutable cell subpopulation (HMS) associated with stress-induced point mutagenesis in the E. coli Lac assay system results from the convergence of cells experiencing both the SOS response (with a DNA double-strand break) and the RpoS response simultaneously. In this version of the model, spontaneous SOS induction and DNA double-strand breakage are constants at the roughly 0.6% level observed in logarithmically growing E. coli cells, with cells cycling into and out of the SOS-induced population at varying rates depicted by curves under the 1% SOS-induced population (Pennington and Rosenberg, 2007). SOS and DSBs are necessary but not sufficient for producing an HMS cell; induction of RpoS, shown as cells enter stationary phase, is also required. This model explains why there is a switch from high-fidelity to error-prone DSBR as cells enter stationary phase or when RpoS is induced (Ponder et al., 2005 and Figure 4).
FIGURE 6
FIGURE 6
Model for amplification induced by rearrangement-provoking replication fork stalling events, and template switching, during acts of DSBR under stress. Model from Slack et al. (2006), and discussed in the text. Single lines represent strands of DNA except in the two circular molecules at the bottom, where they represent whole bacterial chromosomes composed of double-stranded DNA.
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