Starvation Response and RNA Polymerase Guide Antibiotic-induced Mutable Gambler Cells
Starvation Response and RNA Polymerase Guide Antibiotic-induced Mutable Gambler Cells
SUMMARY Antibiotics can induce mutations that cause antibiotic resistance, triggered by stress responses. The identities of the stress-response activators reveal environmental cues that elicit mutagenesis, and are weak links in mutagenesis networks, inhibition of which could slow evolution of resistance during antibiotic therapies. Despite pivotal importance, few identities and fewer functions of stress responses in mutagenesis are clear. Here, we identify the stringent starvation response in fluoroquinolone-antibiotic ciprofloxacin (stress)-induced mutagenesis. We show its role in transient differentiation of a mutable “gambler” cell subpopulation. Stringent activity is induced by reactive oxygen and upregulates two small (s)RNAs that induce the general stress response, which allows mutagenic DNA-break repair. Surprisingly, RNA polymerase and response-activator nucleotide (p)ppGpp promote ciprofloxacin-induced DNA-damage signaling. We propose a model for their regulation of DNA-damage processing in transcribed regions. The data demonstrate a critical node in ciprofloxacin-induced mutagenesis, imply RNA-polymerase regulation of repair, and identify promising targets for resistance-resisting drugs.
Herman Christophe、Rosenberg Susan M.、Garcia-Villada Libertad、Hastings P.J.、Pribis John P.、Minnick P.J.、Zhai Yin
Department of Molecular and Human Genetics, Baylor College of Medicine||Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine||The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine||Department of Molecular Virology and Microbiology, Baylor College of MedicineDepartment of Biochemistry and Molecular Biology, Baylor College of Medicine||Department of Molecular and Human Genetics, Baylor College of Medicine||Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine||The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine||Department of Molecular Virology and Microbiology, Baylor College of Medicine||Systems, Synthetic, and Physical Biology Program, Rice UniversityDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of Medicine||The Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of Medicine||Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of MedicineDepartment of Biochemistry and Molecular Biology, Baylor College of Medicine||Department of Molecular and Human Genetics, Baylor College of MedicineDepartment of Biochemistry and Molecular Biology, Baylor College of Medicine
基础医学微生物学分子生物学
antibiotic resistanceevolutionfluoroquinolonesgeneral stress responsemutationsmutagenic break repairppGppreactive oxygen speciesstress-induced mutagenesisstringent response
Herman Christophe,Rosenberg Susan M.,Garcia-Villada Libertad,Hastings P.J.,Pribis John P.,Minnick P.J.,Zhai Yin.Starvation Response and RNA Polymerase Guide Antibiotic-induced Mutable Gambler Cells[EB/OL].(2025-03-28)[2025-04-27].https://www.biorxiv.org/content/10.1101/2022.07.06.499071.点此复制
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