Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles

Copy-number changes generate phenotypic variability in health and disease. Whether organisms protect against copy-number changes is largely unknown. Here, we show that Saccharomyces cerevisiae monitors the copy number of its ribosomal DNA (rDNA) and rapidly responds to copy-number loss with the clonal amplification of extrachromosomal rDNA circles (ERCs) from chromosomal repeats. ERC formation is replicative, separable from repeat loss, and reaches a dynamic steady state that responds to the addition of exogenous rDNA copies. ERC levels are also modulated by RNAPI activity and diet, suggesting that rDNA copy number is calibrated against the cellular demand for rRNA. Last, we show that ERCs reinsert into the genome in a dosage-dependent manner, indicating that they provide a reservoir for ultimately increasing rDNA array length. Our results reveal a DNA-based mechanism for rapidly restoring copy number in response to catastrophic gene loss that shares fundamental features with unscheduled copy-number amplifications in cancer cells. [Display omitted] •rDNA circles form through a replicative mechanism independent of array instability•Production of rDNA circles anti-correlates with total rDNA copy number•Steady-state level of rDNA circles is regulated by diet and rRNA production•rDNA circles re-insert into the chromosomal rDNA array Copy number variation is associated with both disease and chromosomal evolution. Mansisidor et al. show that healthy yeast cells continuously monitor the copy number of ribosomal DNA repeats and that one strategy for balancing copy number loss is through the amplification of repeats as DNA circles.