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Forkhead Genes in Transcriptional Silencing, Cell Morphology and the Cell Cycle: Overlapping and Distinct Functions for FKH1 and FKH2 in Saccharomyces cerevisiae

Forkhead Genes in Transcriptional Silencing, Cell Morphology and the Cell Cycle: Overlapping and Distinct Functions for FKH1 and FKH2 in Saccharomyces

Forkhead Genes in Transcriptional Silencing, Cell Morphology and the Cell Cycle: Overlapping and Distinct Functions for FKH1 and FKH2 in Saccharomyces cerevisiae   (Citations: 51)
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The SIR1 gene is one of four specialized genes in Saccharomyces cerevisiae required for repressing transcrip- tion at the silent mating-type cassettes, HMLa and HMRa, by a mechanism known as silencing. Silencing requires the assembly of a specialized chromatin structure analogous to heterochromatin. FKH1 was isolated as a gene that, when expressed in multiple copies, could substitute for the function of SIR1 in silencing HMRa. FKH1 (Forkhead Homologue One) was named for its homology to the forkhead family of eukaryotic transcription factors classified on the basis of a conserved DNA binding domain. Deletion of FKH1 caused a defect in silencing HMRa, indicating that FKH1 has a positive role in silencing. Significantly, deletion of both FKH1 and its closest homologue in yeast, FKH2, caused a form of yeast pseudohyphal growth, indicating that the two genes have redundant functions in controlling yeast cell morphology. By several criteria, fkh1D fkh2D-induced pseudohyphal growth was distinct from the nutritionally induced form of pseudohyphal growth observed in some strains of S. cerevisiae. Although FKH2 is redundant with FKH1 in controlling pseudohyphal growth, the two genes have different functions in silencing HMRa. High-copy expression of CLB2, a G2/M-phase cyclin, prevented fkh1D fkh2D-induced pseudohyphal growth and modulated some of the fkhD-induced silencing phenotypes. Interestingly, deletions in either FKH1 or FKH2 alone caused subtle but opposite effects on cell-cycle progression and CLB2 mRNA expression, consistent with a role for each of these genes in modulating the cell cycle and having opposing effects on silencing. The differences between Fkh1p and Fkh2p in vivo were not attributable to differences in their DNA binding domains.
Published in 2000.
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    • ..., show genetic redundancy, as deletion of both genes is necessary to alter growth, cell morphology and gene transcription phenotypes ...

    Spike D. L. Postnikoffet al. The Yeast Forkhead Transcription Factors Fkh1 and Fkh2 Regulate Lifesp...

    • ...In addition, FKH1 and FKH2 also have redundant functions in preventing pseudohyphal growth [56] and silencing...

    Lu Yuet al. Microarray analysis of p -anisaldehyde-induced transcriptome of Saccha...

    • ...FKH1 as a high-copy suppressor of defects in HMRa silencing caused by a sir1 mutation (Hollenhorst et al., 2000)...
    • ...However, paradoxically, the normal role for Fkh1 in wild-type cells seems to be as a negative regulator of CLB2-cluster transcription during G2/M, thus attenuating the level of transcription that can be achieved by Fkh2-mediated activation (Hollenhorst et al., 2000, 2001; Sherriff et al., 2007)...
    • ...Although it is unclear how the role(s) of FKH1 at the CLB2-cluster is related to its ability to affect silencing, it is known that the DNA binding domain of Fkh1 is critical for it ability to modulate SIR1-bypass HMR silencing (Hollenhorst et al., 2000)...
    • ...Unexpectedly (Hollenhorst et al., 2000), the genetic and cell cycle data reported here provide evidence against the role of FKH1 in CLB2 transcription serving as the primary factor in FKH1hc-dependent silencing...
    • ...Five different plasmids were used in this study as indicated in the figure legends: pRS426 (Sikorski and Hieter, 1989), pCF99 (SIR1 in pRS316; Gardner et al., 1999; Hollenhorst et al., 2000), pCF345 (SIR1 in Yep24; Hollenhorst et al., 2000), pCF480 (FKH1 in pRS426; Hollenhorst et al., 2000), and pCF942 (FKH1 in pRS316)...
    • ...Five different plasmids were used in this study as indicated in the figure legends: pRS426 (Sikorski and Hieter, 1989), pCF99 (SIR1 in pRS316; Gardner et al., 1999; Hollenhorst et al., 2000), pCF345 (SIR1 in Yep24; Hollenhorst et al., 2000), pCF480 (FKH1 in pRS426; Hollenhorst et al., 2000), and pCF942 (FKH1 in pRS316)...
    • ...Five different plasmids were used in this study as indicated in the figure legends: pRS426 (Sikorski and Hieter, 1989), pCF99 (SIR1 in pRS316; Gardner et al., 1999; Hollenhorst et al., 2000), pCF345 (SIR1 in Yep24; Hollenhorst et al., 2000), pCF480 (FKH1 in pRS426; Hollenhorst et al., 2000), and pCF942 (FKH1 in pRS316)...
    • ...This probe was also used in a previous study (Hollenhorst et al., 2000)...
    • ...FKH1 is a high-copy suppressor of an HMRa silencing defect caused by a sir1 mutation (Hollenhorst et al., 2000)...
    • ...Expression of FKH1 on a2 vector (FKH1hc) partially restores silencing to these sir1 cells as seen by a reduction in a1 mRNA expressed from HMR-SSa (Hollenhorst et al., 2000; Figure 1A), thus creating SIR1-bypass silencing...
    • ...Third a deletion of FKH1 (fkh1) causes a small but measurable effect on cell cycle progression and CLB2 mRNA levels (Hollenhorst et al., 2000)...
    • ...Fkh2 is the primary transcriptional activator of CLB2-cluster genes (Koranda et al., 2000; Kumar et al., 2000; Pic et al., 2000; Zhu et al., 2000; Reynolds et al., 2003), and a deletion of FKH2 (fkh2) also prolongs the cell cycle and reduces CLB2 mRNA expression (Hollenhorst et al., 2000)...
    • ...Deletion of FKH2 (fkh2) caused a cell cycle defect distinct from that caused by FKH1hc; fkh2 cells showed delayed entry into S phase, but the duration of the remainder of the cell cycle was similar in fkh2 and wildtype cells (Hollenhorst et al., 2000; see Figure 2A, fkh2)...
    • ...These data, combined with earlier analyses of fkh1 cells that produced cell cycle and CLB2 mRNA expression profiles that were the mirror opposite of those produced by FKH1hc (Hollenhorst et al., 2000) also provided evidence that the phenotypes detected in FKH1hc cells reflected a normal role for Fkh1 in vivo...
    • ...What was particularly striking was that the level of FKH1hc-dependent silencing achieved in cells in which either ARS1 or ARSH4 served as the HMR-E silencer was equivalent to that achieved in the HMR-SSa silencer background that was used in the original isolation of FKH1 as a high-copy suppressor of a sir1 mutation (Hollenhorst et al., 2000) (Figure 5B, line 1). That is, for FKH1hc-dependent silencing and in contrast to SIR1-dependent ...
    • ...These data were consistent with the idea, supported by earlier analysis of fkh1 cells (Hollenhorst et al., 2000) that Fkh1 acts as a negative regulator of CLB2 transcription at least during the stages of the cell cycle when CLB2 mRNA expression peaks...

    Laurieann Caseyet al. Conversion of a Replication Origin to a Silencer through a Pathway Sha...

    • ...Conclusion: SADMAMA's utility is demonstrated here by offering a plausible explanation to the differential ARS activity observed in our previous mcm1-1 mutant experiments [1], by suggesting the relevance of multiple weak ACS matches to efficient replication origin function in Saccharomyces cerevisiae, and by suggesting an explanation to the observed negative effect FKH2 has on chromatin silencing [2]...
    • ...Specifically, when overexpressed, Fkh2p is known to have a negative role in silencing the silent mating-type cassette HMRa in S. cerevisiae [2]...
    • ...SADMAMA's utility is demonstrated here by offering a plausible explanation to the differential ARS activity observed in our previous mcm1-1 mutant experiments [1], by suggesting the relevance of multiple weak ACS matches to efficient replication origin function in S. cerevisiae, and by suggesting an explanation to the observed negative effect FKH2 has on chromatin silencing [2]...

    Uri Keichet al. Computational detection of significant variation in binding affinity a...

    • ...Fkh2 and its paralog Fkh1 are redundant activators that bind to the promoters of the CLB2 group of genes expressed in G2, including CLB2, SWI5, and ACE2 (Hollenhorst et al, 2000; Koranda et al, 2000; Kumar et al, 2000; Pic et al, 2000; Zhu et al, 2000)...
    • ...Fkh1/2 (Hollenhorst et al, 2000; Koranda et al, 2000; Kumar et al, 2000; Pic et al, 2000; Zhu et al, 2000), so the nonadditive suppression of the ace2 transcriptional defect in the fkh1 fkh2 double mutant (Figure 1C and D) could be due to decreased SWI5 expression...
    • ...At other times of the cell cycle, Fkh1 and Fkh2, in the absence of Ndd1, actually repress CLB2 transcription (Hollenhorst et al, 2000), an idea supported by the observation that fkh1 mutations suppress the lethality caused by deletion of the NDD1 gene (Koranda et al, 2000)...
    • ...The Fkh1 and Fkh2 proteins have been previously characterized as activators of the G2/M CLB2 group of genes, although they may have negative roles at these genes in other cell cycle phases (Hollenhorst et al, 2000; Kumar et al, 2000; Zhu et al, 2000)...

    Warren P Vothet al. Forkhead proteins control the outcome of transcription factor binding ...

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