%0 Journal Article
%T Topoisomerase I Plays a Critical Role in Suppressing Genome Instability at a Highly Transcribed G-Quadruplex-Forming Sequence
%A Juan Lucas Argueso
%A Margaret Dominska
%A Nayun Kim
%A Puja Yadav
%A Sue Jinks-Robertson
%A Victoria Harcy
%J -
%D 2014
%R 10.1371/journal.pgen.1004839
%X G-quadruplex or G4 DNA is a non-B secondary DNA structure that comprises a stacked array of guanine-quartets. Cellular processes such as transcription and replication can be hindered by unresolved DNA secondary structures potentially endangering genome maintenance. As G4-forming sequences are highly frequent throughout eukaryotic genomes, it is important to define what factors contribute to a G4 motif becoming a hotspot of genome instability. Using a genetic assay in Saccharomyces cerevisiae, we previously demonstrated that a potential G4-forming sequence derived from a guanine-run containing immunoglobulin switch Mu (S¦Ì) region becomes highly unstable when actively transcribed. Here we describe assays designed to survey spontaneous genome rearrangements initiated at the S¦Ì sequence in the context of large genomic areas. We demonstrate that, in the absence of Top1, a G4 DNA-forming sequence becomes a strong hotspot of gross chromosomal rearrangements and loss of heterozygosity associated with mitotic recombination within the ¡«20 kb or ¡«100 kb regions of yeast chromosome V or III, respectively. Transcription confers a critical strand bias since genome rearrangements at the G4-forming S¦Ì are elevated only when the guanine-runs are located on the non-transcribed strand. The direction of replication and transcription, when in a head-on orientation, further contribute to the elevated genome instability at a potential G4 DNA-forming sequence. The implications of our identification of Top1 as a critical factor in suppression of instability associated with potential G4 DNA-forming sequences are discussed
%K Sequence motif analysis
%K Genetic networks
%K Protein structure networks
%K Telomeres
%K DNA replication
%K Gene conversion
%K DNA structure
%K DNA transcription
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004839