Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance

Fitzgerald, Devon M.; Hastings, P. J.; Rosenberg, Susan M.

doi:10.1146/annurev-cancerbio-050216-121919

Cited by 141 publications

(218 citation statements)

References 148 publications

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“…coli in membrane maintenance. These data reinforce the importance and delicacy of stress response regulation of mutagenesis (39; for recent reviews, see references 2, 6, and 10). …”

Section: Discussionsupporting

confidence: 68%

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The Small RNA GcvB Promotes Mutagenic Break Repair by Opposing the Membrane Stress Response

et al. 2016

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Microbes and human cells possess mechanisms of mutagenesis activated by stress responses. Stress-inducible mutagenesis mechanisms may provide important models for mutagenesis that drives host-pathogen interactions, antibiotic resistance, and possibly much of evolution generally. In Escherichia coli, repair of DNA double-strand breaks is switched to a mutagenic mode, using error-prone DNA polymerases, via the SOS DNA damage and general (σS) stress responses. We investigated small RNA (sRNA) clients of Hfq, an RNA chaperone that promotes mutagenic break repair (MBR), and found that GcvB promotes MBR by allowing a robust σS response, achieved via opposing the membrane stress (σE) response. Cells that lack gcvB were MBR deficient and displayed reduced σS-dependent transcription but not reduced σS protein levels. The defects in MBR and σS-dependent transcription in ΔgcvB cells were alleviated by artificially increasing σS levels, implying that GcvB promotes mutagenesis by allowing a normal σS response. ΔgcvB cells were highly induced for the σE response, and blocking σE response induction restored both mutagenesis and σS-promoted transcription. We suggest that GcvB may promote the σS response and mutagenesis indirectly, by promoting membrane integrity, which keeps σE levels lower. At high levels, σE might outcompete σS for binding RNA polymerase and so reduce the σS response and mutagenesis. The data show the delicate balance of stress response modulation of mutagenesis.IMPORTANCE Mutagenesis mechanisms upregulated by stress responses promote de novo antibiotic resistance and cross-resistance in bacteria, antifungal drug resistance in yeasts, and genome instability in cancer cells under hypoxic stress. This paper describes the role of a small RNA (sRNA) in promoting a stress-inducible-mutagenesis mechanism, mutagenic DNA break repair in Escherichia coli. The roles of many sRNAs in E. coli remain unknown. This study shows that ΔgcvB cells, which lack the GcvB sRNA, display a hyperactivated membrane stress response and reduced general stress response, possibly because of sigma factor competition for RNA polymerase. This results in a mutagenic break repair defect. The data illuminate a function of GcvB sRNA in opposing the membrane stress response, and thus indirectly upregulating mutagenesis.

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“…coli in membrane maintenance. These data reinforce the importance and delicacy of stress response regulation of mutagenesis (39; for recent reviews, see references 2, 6, and 10). …”

Section: Discussionsupporting

confidence: 68%

“…Bacterial (1–7), yeast (8), and human cancer (9, 10) cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutation mechanisms may accelerate adaptation specifically when cells are poorly adapted to their environments, i.e., when stressed.…”

Section: Introductionmentioning

confidence: 99%

The Small RNA GcvB Promotes Mutagenic Break Repair by Opposing the Membrane Stress Response

et al. 2016

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“…Plants exposed to (probably) hormetic doses and (certainly) higher sublethal doses of herbicides experience stress, and stress is well known to induce profound physiological changes. Stress‐induced mutagenesis, originally thought to operate only in prokaryotes, is widely documented in plants in response to both biotic and abiotic stressors. Mutations are caused by rapid ROS generation, which causes random breaks in DNA and induces other systemic stress responses .…”

Section: Where Do Ntsr Plants Come From?mentioning

confidence: 99%

Stress‐induced evolution of herbicide resistance and related pleiotropic effects

Dyer

2018

Pest Management Science

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Herbicide-resistant weeds, especially those with resistance to multiple herbicides, represent a growing worldwide threat to agriculture and food security. Natural selection for resistant genotypes may act on standing genetic variation, or on a genetic and physiological background that is fundamentally altered because of stress responses to sublethal herbicide exposure. Stress-induced changes include DNA mutations, epigenetic alterations, transcriptional remodeling, and protein modifications, all of which can lead to herbicide resistance and a wide range of pleiotropic effects. Resistance selected in this manner is termed systemic acquired herbicide resistance, and the associated pleiotropic effects are manifested as a suite of constitutive transcriptional and post-translational changes related to biotic and abiotic stress adaptation, representing the evolutionary signature of selection. This phenotype is being investigated in two multiple herbicide-resistant populations of the hexaploid, self-pollinating weedy monocot Avena fatua that display such changes as well as constitutive reductions in certain heat shock proteins and their transcripts, which are well known as global regulators of diverse stress adaptation pathways. Herbicide-resistant populations of most weedy plant species exhibit pleiotropic effects, and their association with resistance genes presents a fertile area of investigation. This review proposes that more detailed studies of resistant A. fatua and other species through the lens of plant evolution under stress will inform improved resistant weed prevention and management strategies. © 2018 Society of Chemical Industry.

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“…The generality of stress-induced mutation is also demonstrated by findings of similar mechanisms in other organisms, including human cancer cells [reviewed by (Fitzgerald et al 2017)].…”

Section: Assays For Stress-inducible Mutagenic Break Repairmentioning

confidence: 93%

Oxygen and RNA in stress-induced mutation

et al. 2018

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Mechanisms of mutation upregulated by stress responses have been described in several organisms from bacteria to human. These mechanisms might accelerate genetic change specifically when cells are maladapted to their environment. Stress-induced mutation mechanisms differ in their genetic requirements from mutation in growing cells, occurring by different mechanisms in different assay systems, but having in common a requirement for the induction of stress-responses. Here, we review progress in two areas relevant to stress-response-dependent mutagenic DNA break repair mechanisms in Escherichia coli. First, we review evidence that relates mutation to transcription. This connection might allow mutagenesis in transcribed regions, including those relevant to any stress being experienced, opening the possibility that mutations could be targeted to regions where mutation might be advantageous under conditions of a specific stress. We review the mechanisms by which replication initiated by transcription can lead to mutation. Second, we review recent findings that, although stress-induced mutation does not require exogenous DNA-damaging agents, it does require the presence of damaged bases in DNA. For starved E. coli, endogenous oxygen radicals cause these altered bases. We postulate that damaged bases stall the replisome, which, we suggest, is required for DNA-polymerase exchange, allowing the action of low-fidelity DNA polymerases that promote mutation.

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Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance

Cited by 141 publications

References 148 publications

The Small RNA GcvB Promotes Mutagenic Break Repair by Opposing the Membrane Stress Response

The Small RNA GcvB Promotes Mutagenic Break Repair by Opposing the Membrane Stress Response

Stress‐induced evolution of herbicide resistance and related pleiotropic effects

Oxygen and RNA in stress-induced mutation

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