Specific pathways prevent duplication-mediated genome rearrangements

Abstract

SUMMARYWe have investigated the ability of different regions of the left arm of Saccharomyces cerevisiae chromosome V to participate in the formation of gross chromosomal rearrangements (GCRs). We found that the 4.2 kb HXT13 DSF1 region sharing divergent homology with chromosomes IV, X, and XIV, similar to mammalian segmental duplications, was “at-risk” for participating in duplication-mediated GCRs generated by homologous recombination. Numerous genes and pathways, including SGS1, TOP3, RMI1, SRS2, RAD6, SLX1, SLX4, SLX5, MSH2, MSH6, RAD10 and the DNA replication stress checkpoint requiring MRC1 and TOF1 were highly specific for suppressing these GCRs compared to GCRs mediated by single copy sequences. These results indicate that the mechanisms for formation and suppression of rearrangements occurring in regions containing “at risk” sequences differ from those occurring in regions of single copy sequence. This explains how extensive genome instability is prevented in eukaryotic cells whose genomes contain numerous divergent repeated sequences.