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 genes controlling the G1/S transition. It also ensures proper oxidative and cell wall stress responses. Previously, we found that Swi6 was 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 experiments revealed that there was a random genome rearrangement in swi6 Delta cells, whereas in diploid swi6 Delta/swi6 Delta cells, chromosome V is duplicated. SW14 and PAB1, which are located on chromosome V and are known multicopy suppressors of swi6 Delta phenotypes, partially reverse swi6 Delta genome instability when overexpressed. Another gene on chromosome V, RAD51, also supports swi6 Delta survival, but at a high cost; Rad51-dependent illegitimate recombination in swi6 Delta cells appears to connect DSBs, leading to genome rearrangement and preventing cell death. This article has an associated First Person interview with the first author of the paper.