Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine

Abstract

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer.

Roles of Nucleoid-Associated Proteins in Stress-Induced Mutagenic Break Repair in StarvingEscherichia coli

“…Dps-mediated inhibition of MBR was seen for both point (indel) mutation and amplification rates ( Figure 1B). The increased mutagenesis in Ddps cells required known MBR proteins RpoS, RecA, RuvC, and DinB [reviewed in Rosenberg et al (2012)] (Figure 2A). We conclude that increased mutagenesis in Ddps cells reflects increased MBR, not an increase in an alternative mutagenesis mechanism/pathway.…”

“…Repair of DNA double-stranded breaks (DSBs) in E. coli is switched from high fidelity to a mutagenic mode during starvation stress under control of the RpoS general/starvation stress response (Ponder et al 2005;Shee et al 2011;Rosenberg et al 2012). DSB repair switches either to a mutagenic homologous recombination (HR)-mediated repair pathway, using errorprone translesion DNA polymerases IV (DinB or Pol IV) (Ponder et al 2005), Pol V (Petrosino et al 2009;Shee et al 2011), or Pol II (Frisch et al 2010), which creates base substitution and indel mutations [single-nucleotide variations (SNVs)], or to a "micro-homologous" pathway that causes genome rearrangement [gross chromosomal rearrangements (GCRs)] using DNA Pol I [reviewed in Rosenberg et al (2012) and Rogers et al (2015)]. Both SNV and GCR pathways require RecA, RuvC, and RecBC HR proteins.…”

“…Thus, there are three main hubs of stress-response regulation of MBR (Al Mamun et al 2012;Rosenberg et al 2012): (1) formation of a DSB, which RpoE promotes , and its repair, (2) SOS induction, which upregulates DinB about 10-fold transcriptionally , and (3) activation of the RpoS general stress response, which allows DinB and other low-fidelity DNA polymerases to participate in DSB repair by as yet unknown means (Ponder et al 2005;Frisch et al 2010;Shee et al 2011;Rosenberg et al 2012). Previous studies showed that the NAP HU was required for MBR, possibly by promoting HR (Williams and Foster 2007).…”

Stress-induced mutagenesis and complex adaptation

“…Stress-induced mutagenesis (SIM)-the increase of mutation rates in stressed or maladapted individuals-has been demonstrated in several species, including both prokaryotes and eukaryotes [15]. SIM has been observed in laboratory strains [16,17] and natural populations of Escherichia coli [18] (but see [19]), and in other species of bacteria such as pseudomonads [20], Helicobacter pylori [21], Vibrio cholera [22] and Streptococcus pneumonia [23]. SIM has also been observed in yeast [24,25], algae [26], nematodes [27], flies [28] and human cancer cells [29].…”

An Approximate Algorithm Combining P Systems and Active Evolutionary Algorithms for Traveling Salesman Problems

“…So called stress-induced mutation mechanisms were proposed. Specifically, when creatures are maladapted to their environment, that is, when they are stressed, stress-induced mutation mechanisms produce mutations [23][24][25][26]. These facts have been considered in evolutionary algorithm for solving optimization problems [27].…”