Genome rearrangements caused by interstitial telomeric sequences in yeast

Interstitial telomeric sequences (ITSs) are present in many eukaryotic genomes and are linked to genome instabilities and disease in humans. The mechanisms responsible for ITS-mediated genome instability are not understood in molecular detail. Here, we use a model Saccharomyces cerevisiae system to...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 110; no. 49; pp. 19866 - 19871
Main Authors Aksenova, Anna Y., Greenwell, Patricia W., Dominska, Margaret, Shishkin, Alexander A., Kim, Jane C., Petes, Thomas D., Mirkin, Sergei M.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 03.12.2013
NATIONAL ACADEMY OF SCIENCES
National Acad Sciences
SeriesFrom the Cover
Subjects
Biological Sciences
Blotting, Southern
Chromosome Aberrations
Chromosome Fragile Sites - genetics
Chromosomes
DNA
DNA Breaks, Double-Stranded
Genes
Genes, Reporter - genetics
Genetic mutation
Genomes
Genomic Instability - genetics
Introns
Microarray Analysis
Polymerase Chain Reaction
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Telomere - genetics
Telomeres
Yeast
Yeasts
telomere silencing
interstitial telomeres
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Summary:Interstitial telomeric sequences (ITSs) are present in many eukaryotic genomes and are linked to genome instabilities and disease in humans. The mechanisms responsible for ITS-mediated genome instability are not understood in molecular detail. Here, we use a model Saccharomyces cerevisiae system to characterize genome instability mediated by yeast telomeric (Ytel) repeats embedded within an intron of a reporter gene inside a yeast chromosome. We observed a very high rate of small insertions and deletions within the repeats. We also found frequent gross chromosome rearrangements, including deletions, duplications, inversions, translocations, and formation of acentric minichromosomes. The inversions are a unique class of chromosome rearrangement involving an interaction between the ITS and the true telomere of the chromosome. Because we previously found that Ytel repeats cause strong replication fork stalling, we suggest that formation of double-stranded DNA breaks within the Ytel sequences might be responsible for these gross chromosome rearrangements.
Bibliography:http://dx.doi.org/10.1073/pnas.1319313110
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Contributed by Thomas D. Petes, October 11, 2013 (sent for review September 10, 2013)
Author contributions: A.Y.A., T.D.P., and S.M.M. designed research; A.Y.A., P.W.G., M.D., A.A.S., and J.C.K. performed research; A.Y.A., P.W.G., M.D., A.A.S., and J.C.K. contributed new reagents/analytic tools; A.Y.A., P.W.G., M.D., A.A.S., J.C.K., T.D.P., and S.M.M. analyzed data; and A.Y.A., T.D.P., and S.M.M. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1319313110