Bacterial Stationary-State Mutagenesis and Mammalian Tumorigenesis as Stress-Induced Cellular Adaptations and the Role of Epigenetics

Abstract

Mechanisms of cellular adaptation may have some commonalities across different organisms. Revealing these common mechanisms may provide insight in the organismal level of adaptation and suggest solutions to important problems related to the adaptation. An increased rate of mutations, referred as the mutator phenotype, and beneficial nature of these mutations are common features of the bacterial stationary-state mutagenesis and of the tumorigenic transformations in mammalian cells. We argue that these commonalities of mammalian and bacterial cells result from their stressinduced adaptation that may be described in terms of a common model. Specifically, in both organisms the mutator phenotype is activated in a subpopulation of proliferating stressed cells as a strategy to survival. This strategy is an alternative to other survival strategies, such as senescence and programmed cell death, which are also activated in the stressed cells by different subpopulations. Sustained stress-related proliferative signalling and epigenetic mechanisms play a decisive role in the choice of the mutator phenotype survival strategy in the cells. They reprogram cellular functions by epigenetic silencing of cell-cycle inhibitors, DNA repair, programmed cell death, and by activation of repetitive DNA elements. This reprogramming leads to the mutator phenotype that is implemented by error-prone cell divisions with the involvement of Y family polymerases. Studies supporting the proposed model of stress-induced cellular adaptation are discussed. Cellular mechanisms involved in the bacterial stress-induced adaptation are considered in more detail.

Stress-Induced Mutagenesis and Complex Adaptation

“…However, in this scenario the wildtype ab is also stressed and therefore hypermutates with SIM (compare with eq. 1): This scenario has an important biological relevance, as SIM has been implicated in the evolution of drug resistance in bacteria and yeast [34,56,57] and could be involved in the evolution of pathogen virulence and the evolution of drug resistance and progression in cancer cells [58].…”

Stress-induced mutagenesis and complex adaptation

“…This scenario has an important biological relevance, as SIM has been implicated in the evolution of drug resistance in bacteria and yeast [34,70,71], and could be involved in the evolution of pathogen virulence and the evolution of drug resistance and progression in cancer cells [72]. We assume that after the environmental change, the SIM e population has reached a new MSB [56] with mutation rate tU, before the appearance of the double mutant (with s ¼ 0.05 and U ¼ 0.0004, for example, the average number of deleterious mutations is 0.99 .…”

Low pesticide rates may hasten the evolution of resistance by increasing mutation frequencies

“…It is clear that these highly stressed pests that manage to survive a low pesticide dose may have generated a considerable amount of mutant DNA while recuperating. There may even be lasting ‘epigenetic’ alterations: ‘inherited but revocable changes in the genome (without modification of DNA sequences) that lead to metastable changes in gene expression’ 36. These effects are common in bacteria,36 and are also known to be remembered in plants,37, 38 continuing to generate mutations, creating anarchistic mutations and generating a fifth column of highly mutated pests having a higher frequency of all types of pesticide resistance genes.…”

“…There is an abundance of literature showing that various stresses induce mutations in bacteria and in mammalian cells, with various aspects discussed in recent reviews 14, 29, 34–36, 54–56…”