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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

How bacteria and cancer cells regulate mutagenesis and their ability to evolve

Our concept of genomes is changing from one in which the DNA sequence is passed faithfully to future generations to another in which genomes are plastic and responsive to environmental changes. 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, including evolution of infectious disease and cancers, specifically when cells are poorly adapted to their environments—that is, when stressed. Emerging molecular mechanisms of stress-inducible mutagenesis vary but share common components that highlight the non-randomness of mutation: (1) regulation of mutagenesis in time by cellular stress responses, which promote mutations when cells are poorly adapted to their environments—when stressed; (2) limitation of mutagenesis in genomic space causing mutation hotspots and clusters, which may both target specific genomic regions and allow concerted evolution (evolution requiring multiple mutations). This presentation will focus on the molecular mechanism of stress-inducible mutagenic DNA break repair in E. coli as a model for stress-inducible mutagenesis that propels infectious disease, antibiotic resistance, and other evolution. We consider its regulation by stress responses, demonstrate its formation of mutation hotspots near DNA breaks, and our discovery of a large gene network that underlies mutagenic break repair, most of which functions in stress sensing and signaling. We also show that mutagenesis is induced by the antibiotic ciprofloxacin, causing resistance to other antibiotics, and demonstrate the stress-response dependent mutagenesis mechanism. Regulation of mutagenesis in time and genomic space may accelerate evolution including evolution of pathogens, cancers, and drug resistance.

Susan M. Rosenberg

Baylor College of Medicine
Houston, Texas, USA

Email: smr.bcm.bcm@gmail.com