Double‐Strand‐Break Repair, Mutagenesis, and Stress

Rogers, Elizabeth; Correa, Raúl; Barreto, Brittany; Núñez, María Angélica Bravo; Minnick, P.J.; Cruz, Diana Vera; Xia, Jun; Hastings, P. J.; Rosenberg, Susan M.

doi:10.1002/9781119004813.ch15

Cited by 4 publications

(7 citation statements)

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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%

“…We assayed the deletion mutants for MBR proficiency/deficiency using the Lac MBR assay (29). The Lac assay quantifies reversion via MBR of a conjugative-plasmid-borne lac gene with a +1-bp frameshift allele during prolonged starvation for days on minimal lactose solid medium (1–3, 6, 7). Colonies visible on day 2 are roughly 50% preexisting generation-dependent Lac + reversion mutants, and colonies from day 3 onward are DSB-, DinB/Pol IV-, SOS-, σ S -dependent, MBR-generated revertants.…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…In Escherichia coli, repair of DNA double-strand breaks (DSBs) by homologous recombination is switched to a mutagenic mode using error-prone DNA polymerases under the control of the SOS DNA damage response and the general stress response (1, 2, 6, 18–20). Mutagenic break repair (MBR) requires proteins that perform DSB repair via homologous recombination (21–23), low-fidelity DNA polymerases (Pols) IV (18, 19, 24), V (19, 25), and II (26), and the activators of the general/starvation stress response (RpoS/σ S ) (18, 19, 27, 28), the SOS DNA damage response (29, 30), and the RpoE/σ E membrane stress response (31).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2016

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“…The sigma E membrane stress response is required for MBR at some loci (Figure 1, step 1), can be substituted by the delivery of a DSB near the mutation reporter gene assayed, and so promotes spontaneous DSBs, by unknown means (Gibson et al 2010; discussed in Rogers et al 2016). DSB repair (reviewed in Kuzminov 2013) uses human cancer protein analogs and orthologs (Figure 1) (Aravind et al 1999).…”

Section: Mutagenic Break Repair In Escherichia Coli Models Cancer Promentioning

confidence: 99%

Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance

Fitzgerald

Hastings

Rosenberg

2017

Annu. Rev. Cancer Biol.

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Genomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments—that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance.

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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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Double‐Strand‐Break Repair, Mutagenesis, and Stress

Cited by 4 publications

References 91 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 Mutagenesis: Implications in Cancer and Drug Resistance

Oxygen and RNA in stress-induced mutation

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