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

Abstract

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.