Excess histone levels mediate cytotoxicity via multiple mechanisms

Singh, Rakesh Kumar; Liang, Dun; Gajjalaiahvari, Ugander Reddy; Kabbaj, Marie-Helene; Paik, Johanna; Gunjan, Akash

doi:10.4161/cc.9.20.13636

Cited by 124 publications

(130 citation statements)

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“…Given that modest changes in histone levels can have widespread effects on transcription (Norris and Osley 1987;Clark-Adams et al 1988;Singh et al 2010), it is not surprising that yeast histone levels are carefully regulated in vivo.…”

Section: Altering Histone Levels Changes Transcription In Vivomentioning

confidence: 99%

Chromatin and Transcription in Yeast

2012

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Understanding the mechanisms by which chromatin structure controls eukaryotic transcription has been an intense area of investigation for the past 25 years. Many of the key discoveries that created the foundation for this field came from studies of Saccharomyces cerevisiae, including the discovery of the role of chromatin in transcriptional silencing, as well as the discovery of chromatin-remodeling factors and histone modification activities. Since that time, studies in yeast have continued to contribute in leading ways. This review article summarizes the large body of yeast studies in this field.

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Section: Altering Histone Levels Changes Transcription In Vivomentioning

confidence: 99%

Chromatin and Transcription in Yeast

2012

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“…In rad53Δ cells, histone overexpression is lethal because excess histones are not degraded, presumably resulting in aggregation of chromatin (Gunjan and Verreault 2003). Although Rad53 can phosphorylate all four core histones in vitro, it is unclear whether it does this in vivo (Singh et al 2010). Histones associated with Rad53 are both phosphorylated and polyubiquitylated prior to degradation by the proteasome (Singh et al 2010).…”

Section: Regulation Of Histone Degradationmentioning

confidence: 99%

“…Although Rad53 can phosphorylate all four core histones in vitro, it is unclear whether it does this in vivo (Singh et al 2010). Histones associated with Rad53 are both phosphorylated and polyubiquitylated prior to degradation by the proteasome (Singh et al 2010). The reader is referred to the review by Gunjan et al (2006) for further details.…”

Section: Regulation Of Histone Degradationmentioning

confidence: 99%

Regulation of Histone Gene Expression in Budding Yeast

Eriksson¹,

Ganguli²,

Nagarajavel³

et al. 2012

Genetics

116

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We discuss the regulation of the histone genes of the budding yeast Saccharomyces cerevisiae. These include genes encoding the major core histones (H3, H4, H2A, and H2B), histone H1 (HHO1), H2AZ (HTZ1), and centromeric H3 (CSE4). Histone production is regulated during the cell cycle because the cell must replicate both its DNA during S phase and its chromatin. Consequently, the histone genes are activated in late G1 to provide sufficient core histones to assemble the replicated genome into chromatin. The major core histone genes are subject to both positive and negative regulation. The primary control system is positive, mediated by the histone gene-specific transcription activator, Spt10, through the histone upstream activating sequences (UAS) elements, with help from the major G1/S-phase activators, SBF (Swi4 cell cycle box binding factor) and perhaps MBF (MluI cell cycle box binding factor). Spt10 binds specifically to the histone UAS elements and contains a putative histone acetyltransferase domain. The negative system involves negative regulatory elements in the histone promoters, the RSC chromatin-remodeling complex, various histone chaperones [the histone regulatory (HIR) complex, Asf1, and Rtt106], and putative sequence-specific factors. The SWI/SNF chromatin-remodeling complex links the positive and negative systems. We propose that the negative system is a damping system that modulates the amount of transcription activated by Spt10 and SBF. We hypothesize that the negative system mediates negative feedback on the histone genes by histone proteins through the level of saturation of histone chaperones with histone. Thus, the negative system could communicate the degree of nucleosome assembly during DNA replication and the need to shut down the activating system under replication-stress conditions. We also discuss post-transcriptional regulation and dosage compensation of the histone genes.

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“…Consistent with a central role in histone gene expression is the synthetic lethality observed upon loss of the individual SAGA subunits Spt8, Spt20, and Gcn5 with deletion of the histone transcriptional activator Spt10 (Chang and Winston 2013). Normal cell cycle progression and DNA repair require precise regulation of histone levels (Singh et al 2009;Singh et al 2010;Eriksson et al 2012;Liang et al 2012;Ghule et al 2014), therefore restoration of histone expression likely contributes to the restored cell cycle progression and growth upon DNA damage that we observe in gcn5D cells overexpressing RTS1.At the end of S phase, Wee1 phosphorylates H2B-Y40 at histone gene promoters to downregulate expression (Mahajan et al 2012), but a counteracting phosphatase is unknown. Future work should determine whether PP2A Rts1 directly dephosphorylates H2BY40ph as part of the mechanism of histone gene activation.…”

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confidence: 92%

Promotion of Cell Viability and Histone Gene Expression by the Acetyltransferase Gcn5 and the Protein Phosphatase PP2A in Saccharomyces cerevisiae

et al. 2016

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Histone modifications direct chromatin-templated events in the genome and regulate access to DNA sequence information. There are multiple types of modifications, and a common feature is their dynamic nature. An essential step for understanding their regulation, therefore, lies in characterizing the enzymes responsible for adding and removing histone modifications. Starting with a dosagesuppressor screen in Saccharomyces cerevisiae, we have discovered a functional interaction between the acetyltransferase Gcn5 and the protein phosphatase 2A (PP2A) complex, two factors that regulate post-translational modifications. We find that RTS1, one of two genes encoding PP2A regulatory subunits, is a robust and specific high-copy suppressor of temperature sensitivity of gcn5D and a subset of other gcn5D phenotypes. Conversely, loss of both PP2A Rts1 and Gcn5 function in the SAGA and SLIK/SALSA complexes is lethal. RTS1 does not restore global transcriptional defects in gcn5D; however, histone gene expression is restored, suggesting that the mechanism of RTS1 rescue includes restoration of specific cell cycle transcripts. Pointing to new mechanisms of acetylation-phosphorylation cross-talk, RTS1 high-copy rescue of gcn5D growth requires two residues of H2B that are phosphorylated in human cells. These data highlight the potential significance of dynamic phosphorylation and dephosphorylation of these deeply conserved histone residues for cell viability. KEYWORDS chromatin; transcription; phosphorylation; acetylation (IOC2, PAB1, RHO2, MED6, ZDS1, PP2A B56 ) A T the foundation of nuclear DNA organization in eukaryotes is the dynamic formation, movement, and modification of nucleosomes. Acetylation and phosphorylation are two histone post-translational modifications (PTMs) catalyzed by histone acetyltransferases (HATs) and kinases and reversed by histone deacetylases (HDACs) and phosphatases that alter nucleosome structure and function. Tightly regulated acetylation and phosphorylation of specific histone residues have deeply conserved functions in eukaryotes that are critical for transcriptional regulation, replication, repair, and segregation of eukaryotic genomes (Banerjee and Chakravarti 2011;Rossetto et al. 2012;Tessarz and Kouzarides 2014).One well-conserved HAT is Gcn5, which specifically targets histones H3 and H2B as part of multiple complexes (Grant et al. 1997;Eberharter et al. 1999;Grant et al. 1999;Howe et al. 2001;Sterner et al. 2002;Pray-Grant et al. 2005). Gcn5 is a key regulator of eukaryotic gene expression and acetylates H3 at promoters of active genes (Pokholok et al. 2005;Nagy and Tora 2007;Rosaleny et al. 2007). Its role as a transcriptional activator is so fundamental that Gcn5 is essential in most eukaryotes studied. An exception of note is budding yeast, where deletion of GCN5 is tolerated, but does cause a spectrum of phenotypes, including defects in gene activation, particularly for stress-regulated genes, and altered cell cycle progression (Howe et al. 2001;Huisinga and Pugh 2004;Vernarecci ...

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Excess histone levels mediate cytotoxicity via multiple mechanisms

Cited by 124 publications

References 43 publications

Chromatin and Transcription in Yeast

Chromatin and Transcription in Yeast

Regulation of Histone Gene Expression in Budding Yeast

Promotion of Cell Viability and Histone Gene Expression by the Acetyltransferase Gcn5 and the Protein Phosphatase PP2A in Saccharomyces cerevisiae

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