Lack of G1/S control destabilizes the yeast genome via replication stress-induced DSBs and illegitimate recombination.

The protein Swi6 in Saccharomyces cerevisiae is a cofactor in two complexes that regulate the transcription of the G1/S transition genes. It also ensures proper oxidative and cell wall stress responses. Previously, we found Swi6 to be crucial for the survival of genotoxic stress. Here, we show that a lack of Swi6 causes replication stress leading to double-strand break (DSB) formation, inefficient DNA repair, and DNA content alterations, resulting in high cell mortality. Comparative genome hybridization showed random genome rearrangement in swi6Δ , whereas in diploid swi6Δ/swi6Δ , chromosome V is duplicated. SWI4 and PAB1 , known multicopy suppressors of swi6Δ phenotypes located on chromosome V, partially reverse swi6Δ genome instability when overexpressed. Another gene on chromosome V, RAD51 , also supports swi6Δ survival, but at a high cost. Rad51-dependent illegitimate recombination in swi6Δ appears to connect DSBs, leading to genome rearrangement and preventing cell death.