A systematic CEN library of the <i>Saccharomyces cerevisiae</i> genome

Hvorecny, Kelli L.; Prelich, Gregory

doi:10.1002/yea.1783

Cited by 10 publications

(6 citation statements)

References 10 publications

(12 reference statements)

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“…To test whether this phenotypic toggle is in fact modulated by the copy number variation of specific genes, we transformed the original F45 (fluffy) strain with a set of low copy plasmids containing portions of chromosome XVI (34). This screen identified a plasmid containing seven full-length genes that was able to confer the smooth state (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Aneuploidy underlies a multicellular phenotypic switch

Tan

Hays

Cromie

et al. 2013

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

106

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Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the "fluffy" morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the "smooth" colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high-throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. colony morphology | copy number variation | phenotypic switching | bet-hedging

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Section: Resultsmentioning

confidence: 99%

Aneuploidy underlies a multicellular phenotypic switch

Tan

Hays

Cromie

et al. 2013

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

106

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“…Further, the gene responsible for the phenotypic switch was easily identified (Tan et al ., ). This exemplifies the benefit of well‐annotated functional genomics data and a plasmid library of the yeast genome (Hvorecny & Prelich, ) in unraveling the molecular mechanism by which an aneuploid karyotype confers a particular phenotype.…”

Section: Future Perspectivementioning

confidence: 86%

Yeast: a simple model system to study complex phenomena of aneuploidy

Mulla

Zhu

2014

FEMS Microbiol Rev

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Aneuploidy, the state of having a chromosome number different from a multiple of the haploid number, has been associated with diseases and developmental disorders. The role of aneuploidy in human disease pathology, especially in cancer, has been a subject of much attention and debate over the last century due to the intrinsic complexity of the phenomena and experimental challenges. Over the last decade, yeast has been an invaluable model for driving discoveries about the genetic and molecular aspects of aneuploidy. The understanding of aneuploidy has been significantly improved owing to the methods for selectively generating aneuploid yeast strains without causing other genetic changes, techniques for detecting aneuploidy, and cutting-edge genetics and ‘omics’ approaches. In this review, we discuss the contribution of studies in yeast to current knowledge about aneuploidy. Special emphasis is placed on experimental features which make yeast a simpler and efficient model to investigate the complex questions in the field of aneuploidy.

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“…(2) We tested all strains for synthetic lethality with the prp5-SAT-to-GAR allele, which has severely reduced ATPase activity (Xu and Query 2007), identifying seven such strains. We then used a genomic library (Hvorecny and Prelich 2010) to rescue the synthetic lethality. All genomic plasmids that rescued viability carried PRP9 (a U2 snRNP SF3a component), and subsequent sequencing of the PRP9 locus in these strains revealed that all carried an R341K mutation.…”

Section: Mds and Cll Mutations In Sf3b1 Alter Splicing Of Suboptimal mentioning

confidence: 99%

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

et al. 2016

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Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3 ′ splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations. Furthermore, we show that mutations in these motifs from both human disease and yeast genetic screens alter the physical interaction with Prp5p, alter branch region specification, and phenocopy mutations in Prp5p. These and other data demonstrate that mutations in Hsh155p and Prp5p alter splicing because they change the direct physical interaction between Hsh155p and Prp5p. This altered physical interaction results in altered loading (i.e., "fidelity") of the BS-U2 duplex into the SF3B complex during prespliceosome formation. These results provide a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease.

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A systematic CEN library of the Saccharomyces cerevisiae genome

Cited by 10 publications

References 10 publications

Aneuploidy underlies a multicellular phenotypic switch

Aneuploidy underlies a multicellular phenotypic switch

Yeast: a simple model system to study complex phenomena of aneuploidy

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

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