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Mechanobiology of Disease
Tuesday Speaker Abstracts
16
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.