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Genome Rearrangements Caused By Interstitial Telomeric Sequences In Yeast

Anna Y Aksenova, P. Greenwell, M. Dominska, A. Shishkin, Jane C. Kim, T. Petes, S. Mirkin
Published 2013 · Biology, Medicine

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Significance Telomeres are composed of simple repetitive DNA sequences that normally are located at the ends of the chromosomes. Occasionally, however, they also are found inside chromosomes. Some of these internal or interstitial telomeric sequences colocalize with chromosomal fragile sites, preferred sites of breakage in some cancers and hereditary human diseases. The mechanisms responsible for genome instability at interstitial telomeric sequences are unclear. We developed a system to study genetic instabilities caused by these sequences in a model organism (baker’s yeast) that allowed us to characterize various chromosomal rearrangements and to measure the likelihood of their formation. We found that interstitial telomeric sequences promote the formation of deletions, duplications, inversions, and translocations, and we proposed molecular mechanisms responsible for these events. 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.
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