Beyond ERCs: exploring catastrophic forms of rDNA instability in aging yeast
Year: 2026
Type: preprint
Abstract: ABSTRACT 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 structures within the rDNA. We quantified the kinetics of rDNA amplification both as extrachromosomal rDNA circles (ERCs) and as structural forms that are not resolved on CHEF gels. We propose mechanistic models of rDNA instability that describe how both ERCS and other aberrant structures are generated and the unique affects they have on life span. One of the models, which we call Catastrophic IntraChromosomal Repair (CICR), follows the fate of a broken replication fork in the rDNA locus when the template used for repair has already been replicated. At the completion of replication, when all other replication forks have successfully terminated, single, unopposed replication forks remain in the rDNA generating branched DNA molecules that have profound consequences during mitosis and/or subsequent cycles. In addition to ERCs, CICR and related events are additional forms of rDNA instability that contribute to the life span variability in isogenic populations of aging yeast. AUTHOR SUMMARY Aging is an uphill battle against entropy. The wear and tear on biological processes in cells require surveillance mechanisms and repair processes to stave off the inevitable. A cell’s genome is constantly under external and internal insults that can ultimately lead to death. Known events that impact a cell’s DNA are damage from free radicals (produced by the very oxygen needed for survival), shortening of the caps on chromosomes (called telomeres) every time a cell divides, and mutations that accumulate over time that affect essential cell processes. Yeast is an excellent tool to examine specific causes of aging because of its asymmetric mode of cell division: a mother cell can divide a limited, but variable number of times before senescing. We have isolated cohorts of mother cells, examined their genomes over the course of their life span and propose a new intrinsic insult on the genome. We find, in addition to the accumulation of extrachromosomal copies of the genes that encode the RNA portion of ribosomes (rDNA), that cells accumulate toxic runaway replication forks that can results in a branched and/or fragmented chromosome that leads to cell death.
Institution: University of Washington
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7155720006
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