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Non‐homologous end joining as an important mutagenic process in cell cycle‐arrested cells

Resting cells experience mutations without apparent external mutagenic influences. Such DNA replication‐independent mutations are suspected to be a consequence of processing of spontaneous DNA lesions. Using experimental systems based on reversions of frameshift alleles in Saccharomyces cerevisiae, we evaluated the impact of defects in DNA double‐strand break (DSB) repair on the frequency of replication‐independent mutations. The deletion of the genes coding for Ku70 or DNA ligase IV, which are both obligatory constituents of the non‐homologous end joining (NHEJ) pathway, each resulted in a 50% reduction of replication‐independent mutation frequency in haploid cells. Sequencing indicated that typical NHEJ‐dependent reversion events are small deletions within mononucleotide repeats, with a remarkable resemblance to DNA polymerase slippage errors. Experiments with diploid and RAD52‐ or RAD54‐deficient strains confirmed that among DSB repair pathways only NHEJ accounts for a considerable fraction of replication‐independent frameshift mutations in haploid and diploid NHEJ non‐repressed cells. Thus our results provide evidence that G0 cells with unrepressed NHEJ capacity pay for a large‐scale chromosomal stability with an increased frequency of small‐scale mutations, a finding of potential relevance for carcinogenesis.