Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Tuesday Speaker Abstracts

How Bacteria and Cancer Cells Regulate Mutagenesis and Their Ability to Evolve Susan M. Rosenberg . Baylor College of Medicine, Houston, TX, USA. 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. Growing evidence shows that environmental stresses induce mechanisms of genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating evolution including evolution of infectious diseases and cancer. 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 talk will focus on the molecular mechanism of stress-inducible mutagenic DNA break repair in E. coli as a model for mutations that drive cancer 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, a model of cancer chemotherapeutic type-II topoisomerase inhibitors. We find that cipro-induced mutagenesis occurs by a similar stress-inducible mutagenic break-repair mechanism. Regulation of mutagenesis in time and genomic space may accelerate evolution including evolution of cancers.

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