A Genetic and Structural Study of Genome Rearrangements Mediated by High Copy Repeat Ty1 Elements

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.

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“…5D). Indeed, GCRs caused by recombination between Ty or delta elements were observed in many previous studies in yeast (33,34).…”

Section: Discussionmentioning

confidence: 77%

Genome rearrangements caused by interstitial telomeric sequences in yeast

Aksenova

Greenwell

Dominska

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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“…44 A large fraction of transposable elements are encoded within telomeric regions, and increased transposition is often associated with telomere dysfunction. 69 We therefore monitored the transposition of a population of endogenous Ty1 transposable elements to an insertion hotspot upstream of SUF16 using a PCR-based assay, 53,54 in SET1-and SET5-mutant cells, as well as strains deleted for other known and putative histone methyltransferases (Fig. 5B).…”

Section: Set1 and Set5 Promote Telomere Maintenance Pathwaysmentioning

confidence: 99%

The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance

et al. 2017

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Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir proteinindependent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.

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“…Previous studies of chromosomal rearrangements in budding yeast have shown that many rearrangements occur between dispersed copies of homologous retrotransposon sequences in yeast (Louis and Haber 1990;Fischer et al 2000;Lemoine et al 2005;VanHulle et al 2007;Argueso et al 2008;Chan and Kolodner 2011). We wished to determine how often such sequences would be engaged in template switching in BIR events.…”

Section: Frequent Template Switches Between Naturally Repeated Sequencesmentioning

confidence: 99%

Chromosome rearrangements via template switching between diverged repeated sequences

et al. 2014

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Recent high-resolution genome analyses of cancer and other diseases have revealed the occurrence of microhomology-mediated chromosome rearrangements and copy number changes. Although some of these rearrangements appear to involve nonhomologous end-joining, many must have involved mechanisms requiring new DNA synthesis. Models such as microhomology-mediated break-induced replication (MM-BIR) have been invoked to explain these rearrangements. We examined BIR and template switching between highly diverged sequences in Saccharomyces cerevisiae, induced during repair of a site-specific double-strand break (DSB). Our data show that such template switches are robust mechanisms that give rise to complex rearrangements. Template switches between highly divergent sequences appear to be mechanistically distinct from the initial strand invasions that establish BIR. In particular, such jumps are less constrained by sequence divergence and exhibit a different pattern of microhomology junctions. BIR traversing repeated DNA sequences frequently results in complex translocations analogous to those seen in mammalian cells. These results suggest that template switching among repeated genes is a potent driver of genome instability and evolution.

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A Genetic and Structural Study of Genome Rearrangements Mediated by High Copy Repeat Ty1 Elements

Cited by 69 publications

References 71 publications

Genome rearrangements caused by interstitial telomeric sequences in yeast

Genome rearrangements caused by interstitial telomeric sequences in yeast

The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance

Chromosome rearrangements via template switching between diverged repeated sequences

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