Genome Stability under Silence: DNA Repair Networks in Quiescent Fission Yeast

Most of our current understanding of genome integrity derives from studies in proliferating cells, yet most somatic cells in multicellular organisms reside in non-dividing, quiescent states. Using Schizosaccharomyces pombe , we dissected the mechanisms by which quiescent cells maintain genome stability in the absence of DNA replication. Combining time-resolved mutational analyses, DNA damage assays, and genetic dissection of DNA repair pathways, we found that quiescent cells progressively accumulate distinct types of spontaneous lesions-particularly uracil residues, abasic sites, and ribonucleotide insertions-which are counteracted by a modular network of repair mechanisms.

Base excision repair (BER), ribonucleotide excision repair (RER), and R-loop resolution each contribute uniquely to genome surveillance in G0. We show that uracil incorporation becomes a predominant threat under quiescent conditions, especially when nucleotide pools are imbalanced. BER-deficient mutants (e.g., nth1Δ , ung1Δ ) exhibit mutation spectra dominated by C: G > T: A transitions and oxidative lesions, while synthetic combinations reveal compensatory or epistatic interactions. Using single-cell micromanipulation and viability assays, we show that specific gene deletions (e.g., hnt3Δrhp52Δ , sen1Δrad13Δ ) severely compromise post-quiescence recovery, underscoring the importance of cooperative DNA repair even in non-replicative contexts.

Our results delineate a functionally compartmentalized hierarchy of DNA repair activities during quiescence, providing a new framework to understand how non-dividing cells limit genome instability, with implications for aging, cancer dormancy, and neurodegeneration.