Microbes and ageing: Influence of DNA repair

One of the main theories of aging is based on the notion that macromolecular damage in DNA accumulates over time, and that these events could cause many of the phenotypical changes and genome instability seen with the aging process in mammalian organisms. A particular culprit is oxidative stress. Oxidative DNA damage induced by reactive oxygen species (ROS) is a major source of mutation load in living organisms and is believed to play a causative role in aging, neurodegenerative diseases and cancer. To counteract the potential harmful effects of oxidative DNA damage, cells primarily use the base excision repair (BER) pathway. BER is initiated by lesion specific DNA glycosylases which identify and excise the damaged base, leaving an abasic site in the DNA which is further processed by the other enzymes of the BER pathway. Neisseria meningitidis, the meningococcus, is a leading cause of meningitis worldwide. This pathogen faces up to the environment in its exclusive human host with a small but hyperdynamic genome. We constructed meningococcal mutants inactivating genes involved in base excision repair, mismatch repair, nucleotide excision repair, translesion synthesis and recombinational repair pathways. Distinct differences between the meningococcus and the E. coli paradigm for DNA repair in the mutational profiles were identified. In addition to defining roles for neisserial genome dynamics, these findings are important in the context of prokaryotic models linking bacterial mutator phenotypes to cellular fitness, survival under stress and disease. We are currently testing whether the corresponding DNA repair profile in humans develops or attenuates with normal aging and Alzheimer’s disease. Correlating these findings with results of cognitive tests revealed a linkage of certain SNP combinations with memory and attention deficit. Collectively, these findings provide new insight into how both genetic variation and conservation generate a basis for maintaining genome stability and cellular function in the aging process.