Fkh1 and Fkh2 associate with Sir2 to control CLB2 transcription under normal and oxidative stress conditions

Linke, Christian; Klipp, Edda; Lehrach, Hans; Barberis, Matteo; Krobitsch, Sylvia

doi:10.3389/fphys.2013.00173

Cited by 28 publications

(32 citation statements)

References 56 publications

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“…Alternatively, the FHA domain may recruit a rate-limiting initiation factor, which results in the assembly of the origin into a cluster or nascent replication factory. Additionally, Fkh1 and Fkh2 have been reported to recruit chromatin remodelers and histone deacetylases, which are likely to play a role in determining the subnuclear organization of their target loci (Sherriff et al 2007;Veis et al 2007;Voth et al 2007;Linke et al 2013). Future studies will examine the role of chromatin modifiers and remodelers as effectors of Fkh1 and whether Fkh1 regulates subnuclear localization of DNA loci.…”

Section: Fkh1 Programs Replication Origin Timing In G1 Phasementioning

confidence: 98%

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase

et al. 2016

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The Saccharomyces cerevisiae Forkhead Box (FOX) proteins, Fkh1 and Fkh2, regulate diverse cellular processes including transcription, long-range DNA interactions during homologous recombination, and replication origin timing and long-range origin clustering. We hypothesized that, as stimulators of early origin activation, Fkh1 and Fkh2 abundance limits the rate of origin activation genome-wide. Existing methods, however, are not well-suited to quantitative, genome-wide measurements of origin firing between strains and conditions. To overcome this limitation, we developed qBrdU-seq, a quantitative method for BrdU incorporation analysis of replication dynamics, and applied it to show that overexpression of Fkh1 and Fkh2 advances the initiation timing of many origins throughout the genome resulting in a higher total level of origin initiations in early S phase. The higher initiation rate is accompanied by slower replication fork progression, thereby maintaining a normal length of S phase without causing detectable Rad53 checkpoint kinase activation. The advancement of origin firing time, including that of origins in heterochromatic domains, was established in late G1 phase, indicating that origin timing can be reset subsequently to origin licensing. These results provide novel insights into the mechanisms of origin timing regulation by identifying Fkh1 and Fkh2 as rate-limiting factors for origin firing that determine the ability of replication origins to accrue limiting factors and have the potential to reprogram replication timing late in G1 phase.

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Section: Fkh1 Programs Replication Origin Timing In G1 Phasementioning

confidence: 98%

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase

et al. 2016

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“…2A, 2B ) [ 6 , 28 ]; G1 arrested apc5 CA mutants exhibit very low Clb2 levels (Figs. 9A , S4A ); and Fkh proteins normally repress CLB2 expression during G1 [ 19 , 23 ]. Together, this raises the possibility that the higher levels of Fkh1 protein (in G1 arrested APC mutants) could be keeping Clb2 protein levels low through transcriptional repression.…”

Section: Resultsmentioning

confidence: 99%

“…Yeast encode four Fox orthologues: Fkh1, Fkh2, Hcm1 and Fhl1 [ 18 ]. The Fkh1 and Fkh2 transcription factors are evolutionarily conserved, and at least Fkh1 and Fkh2 are redundant [ 5 , 10 , 19 - 21 ]. The Fkhs interact with the transcriptional cofactor Ndd1 in G2 to drive transcription of G2/M genes.…”

Section: Introductionmentioning

confidence: 99%

“…The Fkhs interact with the transcriptional cofactor Ndd1 in G2 to drive transcription of G2/M genes. In G1, Sir2 is recruited to promoters via the Fkh proteins to effect repression of the same key cell cycle progression genes activated earlier during G2 [ 19 , 22 , 23 ]. Because of their redundancy, genomic deletion of both FKH1 and FKH2 genes is required to assess their inherent function.…”

Section: Introductionmentioning

confidence: 99%

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Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance

Malo

Postnikoff

Arnason

et al. 2016

Aging

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The Saccharomyces cerevisiae Forkhead Box (Fox) orthologs, Forkheads (Fkh) 1 and 2, are conserved transcription factors required for stress response, cell cycle progression and longevity. These yeast proteins play a key role in mitotic progression through activation of the ubiquitin E3 ligase Anaphase Promoting Complex (APC) via transcriptional control. Here, we used genetic and molecular analyses to demonstrate that the APC E3 activity is necessary for mitotic Fkh1 protein degradation and subsequent cell cycle progression. We report that Fkh1 protein degradation occurs specifically during mitosis, requires APCCdc20 and proteasome activity, and that a stable Fkh1 mutant reduces normal chronological lifespan, increases genomic instability, and increases sensitivity to stress. Our data supports a model whereby cell cycle progression through mitosis and G1 requires the targeted degradation of Fkh1 by the APC. This is significant to many fields as these results impact our understanding of the mechanisms underpinning the control of aging and cancer.

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“…Closer inspection of the RDT1 promoter indicates an A/T rich region with consensus binding sites for the transcription factors Fkh1/2 and Ash1, each of which regulates mating-type switching [11, 41, 42]. Fkh1 and Fkh2 also physically associate with Sir2 at the mitotic cyclin CLB2 promoter during stress [43]. Ash1 is intriguing because it represses HO transcription in daughter cells [42, 44], raising the possibility of RDT1 repression in daughter cells.…”

Section: Discussionmentioning

confidence: 99%

A Sir2-regulated locus control region in the recombination enhancer ofSaccharomyces cerevisiaespecifies chromosome III structure

Fine

Dinda

et al. 2019

Preprint

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22The NAD + -dependent histone deacetylase Sir2 was originally identified in Saccharomyces 23 cerevisiae as a silencing factor for HML and HMR, the heterochromatic cassettes utilized as 24 donor templates during mating-type switching. MATa cells preferentially switch to MATa using 25 HML as the donor, which is driven by an adjacent cis-acting element called the recombination 26 enhancer (RE). In this study we demonstrate that Sir2 and the condensin complex are recruited to 27 the RE exclusively in MATa cells, specifically to the promoter of a small gene within the right 28 half of the RE known as RDT1. We go on to demonstrate that the RDT1 promoter functions as a 29 locus control region (LCR) that regulates both transcription and long-range chromatin 30interactions. Sir2 represses the transcription of RDT1 until it is redistributed to a dsDNA break at 31 the MAT locus induced by the HO endonuclease during mating-type switching. Condensin is 32 also recruited to the RDT1 promoter and is displaced upon HO induction, but does not 33 significantly repress RDT1 transcription. Instead condensin appears to promote mating-type 34 switching efficiency and donor preference by maintaining proper chromosome III architecture, 35 which is defined by the interaction of HML with the right arm of chromosome III, including 36MATa and HMR. Remarkably, eliminating Sir2 and condensin recruitment to the RDT1 promoter 37 disrupts this structure and reveals an aberrant interaction between MATa and HMR, consistent 38 with the partially defective donor preference for this mutant. Global condensin subunit depletion 39 also impairs mating type switching efficiency and donor preference, suggesting that modulation 40 of chromosome architecture plays a significant role in controlling mating type switching, thus 41 providing a novel model for dissecting condensin function in vivo. 42 43 3 Author summary 44 Sir2 is a highly conserved NAD + -dependent protein deacetylase and defining member of the 45 sirtuin protein family. It was identified about 40 years ago in the budding yeast, Saccharomyces 46 cerevisiae, as a gene required for silencing of the cryptic mating-type loci, HML and HMR. 47These heterochromatic cassettes are utilized as templates for mating-type switching, whereby a 48 programmed DNA double-strand break at the MATa or MATa locus is repaired by gene 49 conversion to the opposite mating type. The preference for switching to the opposite mating type 50 is called donor preference, and in MATa cells, is driven by a cis-acting DNA element called the 51 recombination enhancer (RE). It was believed that the only role for Sir2 in mating-type 52 switching was silencing HML and HMR. However, in this study we show that Sir2 also regulates 53 expression of a small gene (RDT1) in the RE that is activated during mating-type switching. The 54 promoter of this gene is also bound by the condensin complex, and deleting this region of the RE 55 drastically changes chromosome III structure and alters donor preference. The RE therefore 56 appears ...

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Fkh1 and Fkh2 associate with Sir2 to control CLB2 transcription under normal and oxidative stress conditions

Cited by 28 publications

References 56 publications

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase

Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance

A Sir2-regulated locus control region in the recombination enhancer ofSaccharomyces cerevisiaespecifies chromosome III structure

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