In metazoans release of
mitochondrial DNA or
retrotransposon cDNA to cytoplasm can cause sterile
inflammation and disease. Cytoplasmic nucleases degrade these
DNA species to limit
inflammation. It remains unknown whether degradation these
DNA also prevents nuclear
genome instability. To address this question, we decided to identify the nuclease regulating transfer of these cytoplasmic
DNA species to the nucleus. We used an amplicon sequencing-based method in yeast enabling analysis of millions of
DSB repair products. Nu clear mt
DNA (NUMTs) and
retrotransposon cDNA insertions increase dramatically in nondividing stationary phase cells. Yeast EndoG (Nuc1) nuclease limits insertions of
cDNA and transfer of very long
mtDNA (>10 kb) that forms unstable circles or rarely insert in the genome, but it promotes formation of short NUMTs (∼45-200 bp). Nuc1 also regulates transfer of cytoplasmic
DNA to nucleus in aging or during meiosis. We propose that Nuc1 preserves
genome stability by degrading
retrotransposon cDNA and long
mtDNA, while short NUMTs can originate from incompletely degraded
mtDNA. This work suggests that nucleases eliminating cytoplasmic
DNA play a role in preserving
genome stability.