Adaptive mutations in stationary-phase cells
Spontaneous mutations arising in resting cells are likely to contribute to diverse fundamental processes such as the evolution of microorganisms, cellular aging as well as cancerogenesis. In homeostatic tissues there is a strong selective pressure favoring mutations that relieve proliferation-limiting conditions although it may be detrimental to the organism as a whole. Our group is interested in the mechanisms responsible for the formation of such adaptive mutations in stationary-phase cells.
The integrity of genetic information (encoded in the DNA) of each single somatic cell is endangered by spontaneously occurring damage. The DNA is constantly exposed both to random decomposition and to the attack by endogenous reactive substances (e.g. reactive oxygen species as undesirable side products of cellular respiration). Most of the resulting DNA damage can give rise to cancer-initiating and -promoting mutations.
To hinder the development of mutations and to retain the integrity of genetic information, numerous specialized DNA repair mechanisms have developed in the course of evolution. These repair mechanisms perpetually eliminate spontaneous DNA damage, mostly unnoticed in the background, by virtue of an accurate restoration of the initial situation.
However, recent research results place certain DNA repair pathways in the focus of interest, which - in contrast to the majority of repair pathways - in fact eliminate DNA damage but in doing so occasionally introduce mutations into the genome. One intriguing aspect of these pathways is that they may account for mutations arising in resting cells, since they are independent of DNA replication and external influences. Thus, such repair-associated mutagenesis could be a source of cancerogenic mutations in human somatic cells, the majority of which are in a resting state.
Using the budding yeast S. cerevisiae as a model organism, our research group suceeded in identifying a certain DNA repair pathway named non-homologous end joining, which causes a considerable number of mutations during repair of chromosomal breakage in resting cells.
Furthermore, we found and characterized an unexpected mutagenic role (following UV irradiation) of an otherwise accurate repair pathway called nucleotide excision repair. We could also demonstrate that the incidence of abasic sites, of DNA double strand breaks and the intracellular concentration of several reactive oxygen species increases with the duration of cell cycle arrest - and that this increase correlates with the emergence of spontaneous mutations in resting cells.
Ongoing research concentrates on further repair pathways, damage processing and mutagenic mechanisms independent of DNA replication.