Mutation as a Stress Response and the Regulation of Evolvability

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 stressinduced 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.

Condition-dependent sex: who does it, when and why?

“…Other mechanisms that can also increase genetic variation when condition is poor or during stress include mutagenesis [15,88], loss of heterozygosity [89], genomic rearrangements [90], aneuploidy [91,92], dispersal [14,16], mate choice [93] and even death-resulting in the replacement of an aging individual by a young one, generated through sex and mutation [94].…”

LettingEscherichia coliTeach Me About Genome Engineering

“…Together with other colleagues, Genevieve and I were able to identify several regulatory factors involved in the starvation response (RpoS, ClpXP, Lon, HN-S, and Crp) ( Figure 5; Gomez-Gomez et al 1997;Lamrani et al 1999). As has subsequently been discovered for other adaptive mutation systems in bacteria, aerobic starvation leads to signal transduction events and an increase in the genome restructuring activities of transposable elements as well as the SOS system and plasmid transfer functions (Peters and Benson 1995;Taddei et al 1995;Hall 1999;Bjedov et al 2003;Horak et al 2004;Foster 2007;Galhardo et al 2007).…”

DNA polymerases are error-prone at RecA-mediated recombination intermediates

“…6,7 Importantly, stress-induced mutagenesis has many parallels to the adaptation of cancer cells to growth-limiting conditions and stress and therefore may have implications for cancer progression and the ability of tumor cells to develop resistance to therapy. 3 The central mechanism of adaptive mutagenesis in E. coli has been revealed by several years of elegant genetic studies which have identified Y-family translesion DNA polymerase IV (pol IV), also known as DinB, as the major driver of stressinduced mutations. 1,2,8 Pol IV is highly upregulated to ~2500 molecules/cell during the SOS response and is further induced by an additional ~2-fold to ~5000 molecules/cell during stationary phase by the RpoS general stress response.…”

“…[1][2][3] For example, adaptive mutagenesis has been shown to promote antibiotic resistance, which is becoming a major threat to modern medicine. 4,5 It is now evident that stress-induced mutations occur on both episomal and chromosomal DNA and promote the survival of laboratory strains and natural isolates of bacteria under conditions of stress.…”