The potential impact of replication-independent mutagenesis
Cancer is a genetic disease of somatic cells. A progressive accumulation of mutations permits a breakout from growth regulation, enables unlimited proliferation and, finally, spread of cancer cells. On the way from the first breakout from tight regulation to full-blown malignancy, tumor cells have to pass several selective barriers. Overcoming these restraints usually coincides with mutations in certain key genes. However, the number of distinctive genetic modifications observed in most cancer types is too large to be explainable by conventional mutation rates (i.e. per cell division) determined in proliferating cell cultures. A nameable contribution of time-dependent adaptive mutation mechanisms could provide an explanation why mutation rates per cell division derived experimentally are not sufficient to account for the observed numbers of specific mutations in cancer cells. Therefore, it was proposed that many cancer-promoting mutations arise during cell cycle arrest, thus as a function of time, rather than of cell divisions.
Such spontaneous mutagenesis in homeostatic tissues closely resembles a phenomenon originally described in unicellular pro- and eukaryotes. This so-called adaptive mutation is defined as a process that, during non-lethal selection, produces mutations that relieve the selective pressure. Whereas adaptive mutation might considerably contribute to the evolution of microorganisms, the situation is crucially different in multicellular organisms like us. In somatic tissues, mutations that provide a proliferation advantage for the tumorigenic clone may be fatal for the organism as a whole.
My group takes advantage of the model organism Saccharomyces cerevisiae to study the formation of such growth-permitting adaptive mutations in populations of growth-arrested cells and aims to identify the mechanisms responsible for this kind of DNA replication-independent mutagenesis.