Extracellular DNA secreted in yeast cultures is metabolism-specific and inhibits cell proliferation

Extracellular DNA (exDNA) can be actively released by living cells and different putative functions have been attributed to it. Further, homolo-gous exDNA has been reported to exert species-specific inhibitory effects on several organisms. Here, we demonstrate by different experimental evidence, including 1H-NMR metabolomic fingerprint, that the growth rate decline in Saccharomyces cerevisiae fed-batch cultures is determined by the accumula-tion of exDNA in the medium. Sequencing of such secreted exDNA represents a portion of the entire genome, showing a great similarity with extrachromo-somal circular DNA (eccDNA) already reported inside yeast cells. The recov-ered DNA molecules were mostly single strands and specifically associated to the yeast metabolism displayed during cell growth. Flow cytometric analysis showed that the observed growth inhibition by exDNA corresponded to an arrest in the S phase of the cell cycle. These unprecedented findings open a new scenario on the functional role of exDNA produced by living cells.