Beyond ERCs: exploring catastrophic forms of rDNA instability in aging yeast

Single-celled organisms grown in identical conditions have variable life spans. Identifying the factors that drive the inherent variability in life span is crucial for our understanding of aging at a fundamental level. Here, we revisit the role of chromosome XII instability as a source of life span variability in aging populations of the budding yeast, Saccharomyces cerevisiae . We followed populations of mother cells as they aged and quantified changes in karyotype, DNA content, and aberrant DNA structures, including the production of extrachromosomal rDNA circles (ERCs). We found that cells massively amplified their rDNA both as ERCs and as a structural form that could not be resolved on CHEF gels. We propose a model describing how these unresolved structures are generated. Our model, that we call CICR (Catastrophic IntraChromosomal Recombination), describes the consequences of recombination between repeats of different replication status. At the completion of replication, when all other replication forks have successfully terminated, CICR events leave behind a single, unopposed replication fork in a branched form of Chr XII that has profound consequences during mitosis and/or subsequent cycles. This form of instability within the ribosomal DNA can lead to a myriad of toxic recombination products that may contribute to the life span variability in isogenic populations of aging yeast.