Microbial DNA metabolism, genome dynamics and human disease

Abstract

Genetic material is highly dynamic. Genome stability is constantly challenged by endogenous and environmental agents that induce DNA lesions, genome rearrangements and other types of genotoxic stress. At the same time, localized and global mutation events and horizontal gene transfer (HGT) contribute to alterations in DNA. The balancing act between these forces has a major impact on the fitness of cells. While many of the changes generated can be deleterious, the variations they create are the bread and butter of evolutionary processes. During infection of animals, bacterial pathogens encounter DNA-damaging compounds generated by the host as antibacterial defenses. Nitric oxide and reactive oxygen species are particularly important genotoxic agents and generate many DNA lesions. DNA lesions may also accumulate in genomes over time as byproducts of normal metabolic processes. Most such lesions are mended by DNA repair. However, there is still the potential for cumulative unrepaired DNA damage in bacterial genomes, which can play a critical role in generating mutator activity. Our view of microbial DNA metabolism has to a large extent derived from analyses of the model organism Escherichia coli , which has served as a paradigm for DNA repair. However, genome projects have revealed a remarkable variation in gene content among different bacterial species, therefore reflecting differential needs and aims for genetic stability in disparate organisms. Mycobacterium tuberculosis , for instance, compensates for its …