Publication Date
9-3-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-52147-2
PMID
39227600
PMCID
PMC11372161
PubMedCentral® Posted Date
9-3-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Cell Nucleus, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA, Mitochondrial, Endodeoxyribonucleases, Genomic Instability, Meiosis, Retroelements, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Abstract
In metazoans mitochondrial DNA (mtDNA) or retrotransposon cDNA released to cytoplasm are degraded by nucleases to prevent sterile inflammation. It remains unknown whether degradation of these DNA also prevents nuclear genome instability. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products. In non-dividing stationary phase cells, Pol4-mediated non-homologous end-joining increases, resulting in frequent insertions of 1-3 nucleotides, and insertions of mtDNA (NUMTs) or retrotransposon cDNA. Yeast EndoG (Nuc1) nuclease limits insertion of cDNA and transfer of very long mtDNA ( >10 kb) to the nucleus, where it forms unstable circles, while promoting the formation of short NUMTs (~45-200 bp). Nuc1 also regulates transfer of extranuclear DNA to nucleus in aging or meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating extranuclear DNA preserve genome stability.
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