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PubMed1991

Functional interdependence of the yeast SNF2, SNF5, and SNF6 proteins in transcriptional activation.

The SNF2, SNF5, and SNF6 genes of Saccharomyces cerevisiae are required for expression of a variety of differently regulated genes. Previous evidence implicated the SNF5 protein in transcriptional activation, and a DNA-bound LexA-SNF5 fusion protein was shown to activate expression of a nearby promoter. Here, we examine the functional relationship of the SNF2, SNF5, and SNF6 proteins. Activation by DNA-bound LexA-SNF5 fusion protein was greatly reduced in snf2 and snf6 mutants, indicating that activation by LexA-SNF5 requires SNF2 and SNF6 function. An spt6 mutation, which suppresses transcriptional defects caused by snf2, restored activation by LexA-SNF5 in a snf2 mutant. The SNF2 gene was sequenced and encodes a 194-kDa protein that is targeted to the nucleus. DNA-bound LexA-SNF2 fusion protein also activated transcription, dependent on SNF5 and SNF6. These findings suggest that SNF2, SNF5, and SNF6 function interdependently in transcriptional activation, possibly forming a heteromeric complex.

Adenosine Triphosphatases↗

PubMed1990

The SNF5 protein of Saccharomyces cerevisiae is a glutamine- and proline-rich transcriptional activator that affects expression of a broad spectrum of genes.

The Saccharomyces cerevisiae SNF5 gene affects expression of both glucose- and phosphate-regulated genes and appears to function in transcription. We report the nucleotide sequence, which predicts that SNF5 encodes a 102,536-dalton protein. The N-terminal third of the protein is extremely rich in glutamine and proline. Mutants carrying a deletion of the coding sequence were viable but grew slowly, indicating that the SNF5 gene is important but not essential. Evidence that SNF5 affects expression of the cell type-specific genes MF alpha 1 and BAR1 at the RNA level extends the known range of SNF5 function. SNF5 is apparently required for expression of a wide variety of differently regulated genes. A bifunctional SNF5-beta-galactosidase fusion protein was localized in the nucleus by immunofluorescence. No DNA-binding activity was detected for SNF5. A LexA-SNF5 fusion protein, when bound to a lexA operator, functioned as a transcriptional activator.

Amino Acid Sequence↗

PubMed1992

Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure.

Changes in chromatin structure have frequently been correlated with changes in transcription. However, the cause-and-effect relationship between chromatin structure and transcription has been hard to determine. In addition, identifying the proteins that regulate chromatin structure has been difficult. Recent evidence suggests that a functionally related set of yeast transcriptional activators (SNF2/SWI2, SNF5, SNF6, SWI1, and SWI3), required for transcription of a diverse set of genes, may affect chromatin structure. We now present genetic and molecular evidence that at least two of these transcriptional activators, SNF2/SWI2 and SNF5, function by antagonizing repression mediated by nucleosomes. First, the transcriptional defects in strains lacking these SNF genes are suppressed by a deletion of one of the two sets of genes encoding histones H2A and H2B, (hta1-htb1) delta. Second, at one affected promoter (SUC2), chromatin structure is altered in snf2/swi2 and snf5 mutants, and this chromatin defect is suppressed by (hta1-htb1) delta. Finally, analysis of chromatin structure at a mutant SUC2 promoter, in which the TATA box has been destroyed, demonstrates that the differences in SUC2 chromatin structure between SNF5+ and snf5 mutant strains are not simply an effect of different levels of SUC2 transcription. Thus, these results strongly suggest that SNF2/SWI2 and SNF5 cause changes in chromatin structure and that these changes allow transcriptional activation.

Adenosine Triphosphatases↗

PubMed1986

Molecular analysis of SNF2 and SNF5, genes required for expression of glucose-repressible genes in Saccharomyces cerevisiae.

The SNF2 and SNF5 genes are required for derepression of SUC2 and other glucose-repressible genes of Saccharomyces cerevisiae in response to glucose deprivation. Previous genetic evidence suggested that SNF2 and SNF5 have functionally related roles. We cloned both genes by complementation and showed that the cloned DNA was tightly linked to the corresponding chromosomal locus. Both genes in multiple copy complemented only the cognate snf mutation. The SNF2 gene encodes a 5.7-kilobase RNA, and the SNF5 gene encodes a 3-kilobase RNA. Both RNAs contained poly(A) and were present in low abundance. Neither was regulated by glucose repression, and the level of SNF2 RNA was not dependent on SNF5 function or vice versa. Disruption of either gene at its chromosomal locus still allowed low-level derepression of secreted invertase activity, suggesting that these genes are required for high-level expression but are not directly involved in regulation. Further evidence was the finding that snf2 and snf5 mutants failed to derepress acid phosphatase, which is not regulated by glucose repression. The SNF2 and SNF5 functions were required for derepression of SUC2 mRNA.

Cloning, Molecular↗

PubMed1992

Yeast SNF2/SWI2, SNF5, and SNF6 proteins function coordinately with the gene-specific transcriptional activators GAL4 and Bicoid.

The SNF2 (SWI2), SNF5, and SNF6 genes are required for transcription of many diversely regulated genes in Saccharomyces cerevisiae. Previously, we showed that SNF2, SNF5, and SNF6 function interdependently in transcriptional activation, possibly forming a heteromeric complex. Here, we present evidence that SNF6 has a more direct role in stimulating transcription than SNF2 and SNF5. The global effects of mutations in SNF2, SNF5, and SNF6 suggested that these SNF proteins may function coordinately with many gene-specific activators. We show that LexA-GAL4 and LexA-Bicoid fusion proteins are both dependent on SNF2, SNF5, and SNF6 for activation of target genes containing one or multiple lexA operators. The stringency of the requirement for the SNF proteins varies with the activator, the number of binding sites for the activator, and the target promoter. Thus, these SNF proteins appear to represent a class of intermediary proteins that facilitate transcriptional activation by gene-specific regulatory proteins.

Adenosine Triphosphatases↗

PubMed1991

The SNF2, SNF5 and SNF6 genes are required for Ty transcription in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae SNF2, SNF5 and SNF6 genes were initially identified as genes required for expression of SUC2 and other glucose repressible genes. The Suc- defect in all three of these classes of mutants is suppressed by mutations in the SPT6 gene. Since mutations in SPT6 had also been identified as suppressors of Ty and solo delta insertion mutations at the HIS4 and LYS2 loci, we have examined Ty transcription in snf2, snf5 and snf6 mutants and have found that Ty transcription is abolished or greatly reduced. The snf2, snf5 and snf6 defect for Ty transcription, like the defect for SUC2 transcription, is suppressed by spt6 mutations. In contrast to other mutations that abolish or greatly reduce Ty transcription (in the SPT3, SPT7 and SPT8 genes), mutations in these SNF genes do not cause suppression of insertion mutations. This result suggests that the SNF2, SNF5 and SNF6 gene products act by a distinct mechanism from the SPT3, SPT7 and SPT8 gene products to promote transcription of Ty elements. This result also suggests that a reduction of Ty transcription is not always sufficient for activation of adjacent gene expression.

Blotting, Northern↗

PubMed1990

Consequences of growth media, gene copy number, and regulatory mutations on the expression of the PRB1 gene of Saccharomyces cerevisiae.

Glucose represses PRB1 expression at the level of transcription. However, release from glucose repression initially does not result in accumulation of protease B (PrB) activity despite transcriptional derepression. PrB activity accumulates only upon a second transcriptional derepression as the cells approach stationary phase. Increasing the PRB1 gene dosage on 2 mu-based plasmids does not overcome glucose repression. Glucose-mediated repression of PRB1 is not subject to the same genetic controls as SUC2. Mutation of the HXK2 gene, which confers glucose-insensitive expression of secreted invertase, had no effect on PRB1 expression at the level of PrB activity. Strains bearing a mutation in any of the SNF1-SNF6 genes cannot derepress secreted invertase synthesis, but did derepress PrB synthesis when grown in the absence of glucose. Mutation of the SNF2 or SNF5 gene led to accumulation of PrB activity to levels ten times that of wild type. Polymorphism for a suppressor gene was observed: in snf5-bearing strains, one allele of this suppressor gene resulted in elevated levels of PrB and the other allele resulted in wild-type levels of PrB; neither allele suppressed the Suc- phenotype of the snf5 mutant. Re-examination of published data on SUC2 expression in snf2 and snf5 mutants and examination of PRB1 expression in these mutants paradoxically suggest that the SNF2 and SNF5 gene products might act as negative regulators of gene expression.

Culture Media↗

PubMed1986

Suppressors of SNF2 mutations restore invertase derepression and cause temperature-sensitive lethality in yeast.

Mutations in the SNF2 gene of Saccharomyces cerevisiae prevent derepression of the SUC2 (invertase) gene, and other glucose-repressible genes, in response to glucose deprivation. We have isolated 25 partial phenotypic revertants of a snf2 mutant that are able to derepress secreted invertase. These revertants all carried suppressor mutations at a single locus, designated SSN20 (suppressor of snf2). Alleles with dominant, partially dominant and recessive suppressor phenotypes were recovered, but all were only partial suppressors of snf2, reversing the defect in invertase synthesis but not other defects. All alleles also caused recessive, temperature-sensitive lethality and a recessive defect in galactose utilization, regardless of the SNF2 genotype. No significant effect on SUC2 expression was detected in a wild-type (SNF2) genetic background. The ssn20 mutations also suppressed the defects in invertase derepression caused by snf5 and snf6 mutations, and selection for invertase-producing revertants of snf5 mutants yielded only additional ssn20 alleles. These findings suggest that the roles of the SNF2, SNF5 and SNF6 genes in regulation of SUC2 are functionally related and that SSN20 plays a role in expression of a variety of yeast genes.

Enzyme Repression↗

PubMed1992

Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription.

The yeast SWI1, SWI2 (SNF2), and SWI3 genes are required for transcription of HO and INO1 genes. We show that they are also required for transcription of ADH1, ADH2, SUC2, GAL1, and GAL10 and for function of simple UAS elements with binding sites for yeast GAL4 or Drosophila ftz proteins. SWI3 encodes a 99 kd nuclear protein containing a large, highly acidic N-terminal domain. SWI1 is identical to ADR6, which encodes a positive regulator of ADH1 and ADH2. Transcription of HO also requires SNF5 and SNF6. These and other observations suggest that SWI1, SWI2, SWI3, SNF5, and SNF6 may be components of a large multi-subunit complex. We propose that these products perform a general role in transcription by assisting gene-specific regulatory proteins.

Amino Acid Sequence↗

PubMed2025

MYC Regulates a DNA Repair Gene Expression Program in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.

BACKGROUND/OBJECTIVES: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to the SMARCA4 gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by the MYC oncogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. METHODS: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. RESULTS: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. CONCLUSIONS: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.

ATR↗

PubMed1992

Chromatin structure of the yeast SUC2 promoter in regulatory mutants.

We have previously suggested that two positioned nucleosomes are removed from the promoter of the Saccharomyces cerevisiae SUC2 gene upon depression by glucose starvation. To gain further insight into the changes accompanying derepression at the chromatin level we have studied the chromatin structure of the SUC2 promoter in several mutants affecting SUC2 expression. The non-derepressible mutants snf1, snf2 and snf5 present a chromatin structure characteristic of the repressed state, irrespective of the presence or absence of glucose. The non-repressible mutants, mig1 and ssn6, as well as the double mutant snfs sn6 exhibit an opened chromatin structure even in the presence of glucose. These results suggest that the DNA-binding protein encoded by MIG1 is necessary to produce the characteristic pattern of repressed chromatin and that the SNF1 protein kinase is sufficient to produce the derepressed chromatin pattern. A model is presented for the transitions that result in opening up of the chromatin structure.

Base Sequence↗

PubMed1991

Characterization of trans-acting mutations affecting Ty and Ty-mediated transcription in Saccharomyces cerevisiae.

By recessive mutations, we have identified five genes, TYE1-TYE5, that are required for Ty-mediated expression of ADH2. These tye mutations not only suppress transcription of ADH2 when associated with a Ty element but are also defective in transcription of all Ty1 and Ty2 elements. Moreover, some of these mutations cause growth defects on non-fermentable carbon sources as well as sporulation defects. tye mutations also strongly suppress ADH2 expression when controlled by a polyA/T insertion mutation. Genetic analysis revealed that genes TYE3 and TYE4 are allelic to the previously identified genes SNF2 and SNF5 which code for transcription factors. These findings suggest that TYE gene products influence transcription of many genes rather than specifically Ty and Ty-mediated transcription. We have also found that null alleles of certain STE genes (ste7, ste11 and ste12), known to affect cell-type specific gene expression and expression of some Ty-adjacent genes, have a clear effect on Ty-controlled ADH2 expression depending on the carbon source. On the basis of ADH2 transcript levels in glucose-grown cells, all three ste alleles cause of five-fold reduction of ADH2 expression/transcription. In ethanol-grown cells, ste11 and ste12 mutations caused an almost complete loss of Ty-mediated ADH2 activation while ste7 has only a rather moderate effect. Surprisingly, ste11 and ste12 mutations lead to a significant increase in total Ty transcript levels. This would indicate that the STE12 protein, which is known to bind specifically to Ty1 sequences and thereby serve as an activator of a Ty-adjacent gene, can negatively modulate Ty transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗

PubMed1988

High-affinity glucose transport in Saccharomyces cerevisiae is under general glucose repression control.

Saccharomyces cerevisiae mutants defective in growth on low glucose concentration (lgn mutants) were isolated and screened for abnormal glucose transport. Nine complementation groups were identified, falling into two broad groups: those unable to significantly derepress high-affinity (low-Km) glucose uptake (lgn1, lgn4, lgn5, lgn7, and lgn8), and those with elevated repressed levels of high-affinity uptake that either derepress to normal or near normal levels of high-affinity uptake with loss of low-affinity transport (lgn2 and lgn3) or derepress only slightly, appearing to have an intermediate yet constitutive level of high-affinity transport (lgn6 and lgn9). Further analysis of the lgn mutations revealed pleiotropic phenotypes most consistent with the true defect being in regulation or expression of glucose repression and derepression. The kinetics of glucose uptake in strains carrying known mutations preventing derepression of glucose-repressible functions (snf1, snf2, snf4, and snf6) demonstrated that three of these mutations (snf1, snf4, and snf6) were similarly defective in derepression of high-affinity glucose uptake. The snf2 and snf5 mutations had no apparent effect on glucose uptake. Two mutations resulting in constitutive expression of glucose-repressible functions, cid1 and reg1, resulted in constitutive expression of high-affinity glucose uptake. These data support the conclusion that high-affinity glucose uptake in Saccharomyces cerevisiae is under general glucose repression control. The implications of other properties of these mutants are discussed.

Biological Transport↗

PubMed1990

SNF6 encodes a nuclear protein that is required for expression of many genes in Saccharomyces cerevisiae.

The SNF6 gene appears to affect transcription from a variety of promoters in Saccharomyces cerevisiae. The gene was cloned, and sequence analysis revealed two completely overlapping open reading frames of 996 and 1092 nucleotides on opposite strands. The SNF6 coding sequence was identified by selective mutagenesis. The predicted 37,604-dalton SNF6 protein is highly charged but overall neutral. A bifunctional SNF6-beta-galactosidase fusion protein was localized in the nucleus, as judged by immunofluorescence microscopy. The N terminus of SNF6 contains a sequence homologous to nuclear localization signals and was sufficient to direct beta-galactosidase to the nucleus. The 5' ends of the SNF6 RNA were heterogeneous and included ends mapping downstream from the first ATG codon. Construction of a frameshift mutation provided evidence that translational initiation at the second ATG yields a partially functional SNF6 product. Null mutations in SNF6 caused a wider range of pleiotropic defects than the previously isolated point mutation, including slow growth. Genetic and molecular evidence suggested that SNF6 is functionally related to the SNF2 and SNF5 genes. These genes may function together to affect transcription.

Alleles↗

PubMed1987

SSN20 is an essential gene with mutant alleles that suppress defects in SUC2 transcription in Saccharomyces cerevisiae.

Dominant and recessive mutations at the SSN20 locus were previously isolated as extragenic suppressors of mutations in three genes (SNF2, SNF5, and SNF6) that are required in trans to derepress invertase expression. All ssn20 alleles cause recessive, temperature-sensitive lethality. In this study we cloned the SSN20 gene, identified a 4.6-kilobase poly(A)-containing RNA, and showed that disruption of the gene is lethal in a haploid cell. Genetic mapping of SSN20 to a locus on chromosome VII 10 centimorgans distal to cly8 led to the finding that SSN20 is the same gene as SPT6, which affects expression of delta insertions in the 5' noncoding region of HIS4 (F. Winston, D. T. Chaleff, B. Valent, and G. R. Fink, Genetics 107:179-197, 1984). We also showed that an ssn20 mutation restored expression of secreted invertase from deletions of the SUC2 upstream regulatory region; ssn20 restored derepression of SUC2 mRNA in strains with a SUC2 upstream region deletion or a snf2 mutation. Increased or decreased gene dosage of SSN20 also suppressed defects that are suppressed by ssn20 missense mutations. These findings suggest that SSN20 plays a role in general transcriptional processes.

Chromosome Mapping↗

PubMed1987

The SPT6 gene is essential for growth and is required for delta-mediated transcription in Saccharomyces cerevisiae.

Mutations in the Saccharomyces cerevisiae SPT6 gene were originally identified as one class of extragenic suppressors of Ty and delta insertion mutations in the 5' noncoding regions of HIS4 and LYS2. We cloned SPT6 and constructed a null allele by gene disruption. Haploid spores carrying the spt6 null allele were inviable, indicating that the SPT6 gene is essential for mitotic growth. SPT6 was mapped to the right arm of chromosome VII, 44 centimorgans (cM) from ADE6 and 9 cM from CLY8. We showed that spt6 mutations suppress delta insertion mutations at the level of transcription but have no qualitative or quantitative effect on Ty transcription. In addition, we observed interesting SPT6 gene dosage effects. An SPT6 strain containing a high-copy-number plasmid clone of SPT6 showed suppression of delta insertion mutations, and a diploid strain with half its normal dose of SPT6 (SPT6/spt6 null) also exhibited suppression of delta insertion mutations. Therefore, having either too many or too few copies of SPT6 causes a mutant phenotype. Finally, this study and that in the accompanying paper (L. Neigeborn, J. L. Celenza, and M. Carlson, Mol. Cell. Biol. 7:679-686, 1986) showed that spt6 and ssn20 mutations (isolated as suppressors of snf2 and snf5 [sucrose nonfermenting] mutations) identify the same gene. SPT6 and SSN20 have the same genetic map position and share an identical restriction map. Furthermore, spt6 and ssn20 mutations fail to complement each other, and ssn20 mutations suppress solo delta insertion mutations at HIS4 and LYS2. These results, taken in conjunction with the SPT6 dosage effects and the fact that SPT6 is an essential gene, suggest that SPT6 plays a fundamental role in cellular transcription, perhaps by interaction with other transcription factors.

Alleles↗