DNase II, identified in 1947 and named in 1953, is an acidic DNA endonuclease prevalent across organisms and crucial for normal growth. Despite its expression in nearly all human tissues, as well as its biological significance, DNase II’s detailed functions and corresponding mechanisms remain unclear. Although many groups are trying to figure this out, progress is very limited. It is very hard to connect its indispensability with its DNA cleavage activity. In this study, we find that DNase II secreted to saliva can digest RNA in mildly acidic conditions, prompting us to hypothesize that salivary DNase II might digest RNA in the stomach. This finding is consistent with the interesting discovery reported in 1964 that RNA could inhibit DNase II’s activity, which has been largely overlooked. This RNA digestion activity is further confirmed by using purified DNase II, showing activity to digest both DNA and RNA effectively. Here, we suggest redesignating DNase II as DNase II (RNase). The biological functions of DNase II are suggested to recycle intracellular RNA or digest external nucleic acids (both RNA and DNA) as nutrients. This discovery may untangle the mystery of DNase II and its significant biofunctions.

Nucleic acids are significant components of daily diet and have attracted attention regarding their metabolic and nutritional roles. Numerous studies have explored the biological functions of nucleotides, nucleosides, and functional nucleic acids like microRNAs. However, the nutritional value and metabolic mechanisms of RNA oligonucleotides derived from ribosomal RNA (rRNA)—a major form of nucleic acids in nature remain underexplored. Here, yeast was utilized as a model organism to investigate the absorption and metabolism of oligonucleotides obtained from rRNA. We cultured yeast directly using RNA oligonucleotides as one nutrient, demonstrating that yeast can efficiently utilize RNA oligonucleotides (length < 30 nt) as a nitrogen source. Through proteomic analysis to assess the expression levels of key proteins associated with transport and metabolic processes, we found that the key proteins involved in endocytosis, autophagy, and RNA degradation were upregulated. These results clearly demonstrate that yeast directly uptakes RNA oligonucleotides via endocytosis, which are subsequently degraded into nucleosides, ammonia and β-Alanine through autophagy and RNA degradation, thus providing substrates for synthesizing nucleic acid and other organic nitrogenous metabolites. Our findings and proposed mechanisms for RNA absorption and metabolism in eukaryotic cells can promote future research in both nutrition and nucleic acid metabolism.

Nucleic acids are essential dietary components with diverse physiological functions. Numerous studies have focused on the biological functions of nucleotides, nucleosides, and functional RNAs such as microRNAs. However, the nutritional value of ribosomal RNA (rRNA)-derived oligonucleotides, which are likely the predominant nucleic acid-derived components in foods, remains largely unexplored. Here, yeast was used as a food-associated eukaryotic model organism to investigate the uptake and utilization of rRNA-derived oligonucleotides. Yeast efficiently utilized short RNA oligonucleotides (approximately 5–30 nt) as nutrient sources, supporting robust cell growth. Confocal microscopy confirmed rapid uptake of Cy5-labeled RNA oligonucleotides by yeast cells. Proteomic analysis further revealed marked upregulation of proteins involved in endocytosis and autophagy in yeast cultured with RNA oligonucleotides. Collectively, these findings demonstrate that yeast can internalize and metabolize rRNA-derived oligonucleotides as efficient nutrient sources, likely through coordinated endocytic and autophagic pathways. This study highlights the nutritional potential of rRNA-derived oligonucleotides and provides a foundation for their future application in functional foods and fermentation systems.