Retrotransposon overdose and genome integrity

Scheifele, Lisa Z.; Cost, Gregory J.; Zupancic, Margaret L.; Caputo, Emerita M.; Boeke, Jef D.

doi:10.1073/pnas.0906552106

Cited by 31 publications

(29 citation statements)

References 40 publications

(34 reference statements)

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“…No breakpoints were detected at singlecopy or microhomology sequences. This pattern was consistent with several other studies that implicated Ty sequences as hotspots for chromosomal rearrangements Scheifele et al 2009) and confirmed that NAHR is the primary DSB repair pathway responsible for such events in yeast. Interestingly, the spontaneous rearrangements selected in the CFR diploid clones were reminiscent of those we found in isogenic, G2-synchronized diploids that survived exposure to 800 Gy of ionizing radiation resulting in 250 DSBs per cell .…”

Section: A New Assay For Copy-number Variationsupporting

confidence: 80%

Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

et al. 2013

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The increasing ability to sequence and compare multiple individual genomes within a species has highlighted the fact that copy-number variation (CNV) is a substantial and underappreciated source of genetic diversity. Chromosome-scale mutations occur at rates orders of magnitude higher than base substitutions, yet our understanding of the mechanisms leading to CNVs has been lagging. We examined CNV in a region of chromosome 5 (chr5) in haploid and diploid strains of Saccharomyces cerevisiae. We optimized a CNV detection assay based on a reporter cassette containing the SFA1 and CUP1 genes that confer gene dosage-dependent tolerance to formaldehyde and copper, respectively. This optimized reporter allowed the selection of low-order gene amplification events, going from one copy to two copies in haploids and from two to three copies in diploids. In haploid strains, most events involved tandem segmental duplications mediated by nonallelic homologous recombination between flanking direct repeats, primarily Ty1 elements. In diploids, most events involved the formation of a recurrent nonreciprocal translocation between a chr5 Ty1 element and another Ty1 repeat on chr13. In addition to amplification events, a subset of clones displaying elevated resistance to formaldehyde had point mutations within the SFA1 coding sequence. These mutations were all dominant and are proposed to result in hyperactive forms of the formaldehyde dehydrogenase enzyme.A S a consequence of studies that utilize genomic microarrays and next-generation DNA sequencing, it has become clear that much of the natural genetic variation that exists between individuals is due to alterations in the number of copies of genes rather than differences in the nucleotide sequence (Girirajan et al. 2011;Veltman and Brunner 2012). It has been calculated that 8-25 kb of DNA are deleted or duplicated per generation in humans compared to about 100 bp of point mutations (Itsara et al. 2010). Although deletions and duplications vary in size from a few base pairs (for example, changes in the lengths of microsatellites) to many megabases (for example, changes in ploidy), Girirajan et al. (2011) define copy-number variants (CNVs) in humans as changes that vary in size between 50 bp and 1 Mb. While most CNV events have no obvious effect, a significant number are associated with human diseases including Charcot-Marie-Tooth syndrome, autosomal dominant leukodystrophy, Williams syndrome, several cancer predispositions, and autism-related and other neurodevelopmental disorders (Abrahams and Geschwind 2008;Girirajan et al. 2011;Krepischi et al. 2012;Malhotra and Sebat 2012;Sullivan et al. 2012). There is also strong evidence suggesting that CNVs played a significant role in human evolution (Iskow et al. 2012). Finally, multiple somatic CNV events are frequently observed in the altered karyotypes of cancer cells (Stratton et al. 2009).CNVs have also been widely observed in natural populations and have been studied in detail in model organisms. In the discussion below, w...

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Section: A New Assay For Copy-number Variationsupporting

confidence: 80%

Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

et al. 2013

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“…The extreme inhibitory effect and broad dynamic range raise the possibility that the process of retrotransposition is very sensitive to the level of p22, with increasingly severe defects appearing as the level of p22 increases. Conversely, the relative amount of Ty1 versus p22 expression can likely saturate the inhibitor, as is evident from previous studies utilizing GAL1-promoted Ty1 induction (15,16,33,34). In fact, Ty1 "transpositional dormancy," which was described upon the discovery of Ty1 retrotransposition (15,34), may result from an inhibitor that is saturated or overcome when Ty1 is induced via the GAL1 promoter (73)(74)(75).…”

Section: Discussionmentioning

confidence: 82%

“…cerevisiae and S. paradoxus laboratory strains and natural isolates contain fewer than 40 copies of Ty1 per haploid genome, and several strains contain few if any elements (5,(10)(11)(12)(13)(14). Although budding yeast genomes characterized to date tend to have low Ty1 copy numbers, fertile S. cerevisiae strains containing more than 100 Ty1 insertions have been created artificially by numerous rounds of induction of a multicopy plasmid containing an active Ty1 element (Ty1H3) fused to the GAL1 promoter (pGTy1) (15,16). Host cofactor and restriction genes involved in modulating Ty1 retrotransposition are diverse and encompass different steps in the replication cycle, ranging from transcription to integration site preference (17)(18)(19)(20)(21).…”

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confidence: 99%

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

Saha

Mitchell

Nishida

et al. 2015

J Virol

232

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Saccharomyces cerevisiae and Saccharomyces paradoxus lack the conserved RNA interference pathway and utilize a novel form of copy number control (CNC) to inhibit Ty1 retrotransposition. Although noncoding transcripts have been implicated in CNC, here we present evidence that a truncated form of the Gag capsid protein (p22) or its processed form (p18) is necessary and sufficient for CNC and likely encoded by Ty1 internal transcripts. Coexpression of p22/p18 and Ty1 decreases mobility more than 30,000-fold. p22/p18 cofractionates with Ty1 virus-like particles (VLPs) and affects VLP yield, protein composition, and morphology. Although p22/p18 and Gag colocalize in the cytoplasm, p22/p18 disrupts sites used for VLP assembly. Glutathione Stransferase (GST) affinity pulldowns also suggest that p18 and Gag interact. Therefore, this intrinsic Gag-like restriction factor confers CNC by interfering with VLP assembly and function and expands the strategies used to limit retroelement propagation. IMPORTANCERetrotransposons dominate the chromosomal landscape in many eukaryotes, can cause mutations by insertion or genome rearrangement, and are evolutionarily related to retroviruses such as HIV. Thus, understanding factors that limit transposition and retroviral replication is fundamentally important. The present work describes a retrotransposon-encoded restriction protein derived from the capsid gene of the yeast Ty1 element that disrupts virus-like particle assembly in a dose-dependent manner. This form of copy number control acts as a molecular rheostat, allowing high levels of retrotransposition when few Ty1 elements are present and inhibiting transposition as copy number increases. Thus, yeast and Ty1 have coevolved a form of copy number control that is beneficial to both "host and parasite." To our knowledge, this is the first Gag-like retrotransposon restriction factor described in the literature and expands the ways in which restriction proteins modulate retroelement replication.

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“…The majority of the mono-nucleosomal γH2AX sites (67.3% in SR and 65.8% in SEN) were associated with the retrotransposal portion of the genome, with SINEs contributing 34.9% and 30.0% and LINEs accounting for 32.4% and 35.8% of these sites in SR and SEN hADSCs, respectively (Table S1). Because the retrotransposon portion of the genome is known to impede the progression of replication machinery, [23][24][25] a portion of γH2AX detected in asynchronously dividing cells (the SR sample) might be caused by replication-fork pausing or collapse as described previously in yeast. 23,[26][27][28] Our data also indicates that the majority of damage in SEN cells is not related to unrepaired damage accumulation caused by the collision of replication forks Chromosome 10 showed an increase of pericentric γH2AX tag accumulation in the SEN sample, including an excess of large clusters, whereas chromosome 21 had more pericentric γH2AX in the SR sample (Fig.…”

confidence: 99%

Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal

et al. 2011

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Retrotransposon overdose and genome integrity

Cited by 31 publications

References 40 publications

Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal

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