Yeast EndoG prevents genome instability by degrading extranuclear DNA species

Yang Yu, Xin Wang, Jordan Fox, Ruofan Yu, Pilendra Thakre, Brenna McCauley, Nicolas Nikoloutsos, Yang Yu, Qian Li, P. J. Hastings, Weiwei Dang, Kaifu Chen () and Grzegorz Ira ()
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Yang Yu: Baylor College of Medicine
Xin Wang: Boston Children’s Hospital
Jordan Fox: Baylor College of Medicine
Ruofan Yu: Baylor College of Medicine
Pilendra Thakre: Baylor College of Medicine
Brenna McCauley: Baylor College of Medicine
Nicolas Nikoloutsos: Baylor College of Medicine
Yang Yu: Boston Children’s Hospital
Qian Li: Baylor College of Medicine
P. J. Hastings: Baylor College of Medicine
Weiwei Dang: Baylor College of Medicine
Kaifu Chen: Boston Children’s Hospital
Grzegorz Ira: Baylor College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52147-2

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