Multiple histone modifications in euchromatin promote heterochromatin formation by redundant mechanisms in Saccharomyces cerevisiae

Verzijlbergen, Kitty F.; Faber, Alex W.; Stulemeijer, I.J.E.; Leeuwen, Fred van

doi:10.1186/1471-2199-10-76

Cited by 27 publications

(33 citation statements)

References 100 publications

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“…Acetylation of H3K9 and K14 and phosphorylation of H3S10 are also reduced but follow the total H3 profile and are therefore unlikely to represent separate defects. The H3 and H2B total protein profiles are similar, suggesting coregulation of H3 and H2B that is dependent on Elp3 and Gcn5 (64). However, the addition of the apc5 CA allele modestly influenced total H3 levels only in elp3⌬ cells.…”

Section: Resultsmentioning

confidence: 71%

The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

Turner¹,

Malo²,

Pisclevich³

et al. 2010

Eukaryot Cell

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The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G 1 . Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific set of posttranslational histone-modifying enzymes. Multiple APC subunit mutants were impaired in total and modified histone H3 protein content. Acetylated H3K56 (H3K56 Ac ) levels were as reduced as those of total H3, indicating that loading histones with H3K56 Ac is unaffected in APC mutants. However, under restrictive conditions, H3K9Ac and dimethylated H3K79 (H3K79 me2 ) levels were more greatly reduced than those of total H3. In a screen for histone acetyltransferase (HAT) and histone deacetylase (HDAC) mutants that genetically interact with the apc5 CA (chromatin assembly) mutant, we found that deletion of GCN5 or ELP3 severely hampered apc5 CA temperature-sensitive (ts) growth. Further analyses showed that (i) the elp3⌬ gcn5⌬ double mutant ts defect was epistatic to that observed in apc5 CA cells; (ii) gcn5⌬ and elp3⌬ mutants accumulate in mitosis; and (iii) turnover of the APC substrate Clb2 is not impaired in elp3⌬ gcn5⌬ cells. Increased expression of ELP3 and GCN5, as well as genes encoding the HAT Rtt109 and the chromatin assembly factors Msi1 and Asf1, suppressed apc5 CA defects, while increased APC5 expression partially suppressed elp3⌬ gcn5⌬ growth defects. Finally, we demonstrate that Gcn5 is unstable during G 1 and following G 1 arrest and is stabilized in APC mutants. We present our working model in which Elp3/Gcn5 and the APC work together to facilitate passage through mitosis and G 1 . To progress into S, we propose that at least Gcn5 must then be targeted for degradation in an APC-dependent fashion.

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Section: Resultsmentioning

confidence: 71%

The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

Turner¹,

Malo²,

Pisclevich³

et al. 2010

Eukaryot Cell

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“…Euchromatin allows transcription and is characterized by acetylated (H3K9-Ac and H4K16-Ac) and methylated (H3K4me3, and H3K79me2) histone H3 and H4 (35). Heterochromatin, on the contrary, inhibits RNA synthesis and is characterized by a different set of chromatin marks such as di-and trimethylated H3K9 (H3K9me2-3) and H3K27 (H3K27me2), the recruitment of histone H1, in addition to the loss of euchromatic acetylation and methylation marks (36)(37)(38)(39). As XP-D/CS cells were unable to restart the transcription of HK genes after UV irradiation, we thus monitored these promoters at the chromatin level.…”

Section: Xp-d/cs Cells Elicit Transcriptional Stress Response Upon Uvmentioning

confidence: 99%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

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“…Dot1 deletion or overexpression reduces silencing at the telomere, silent mating-type loci, and ribosomal DNA loci (4,9). Beyond the repetitive regions, Dot1 is also known to regulate heterochromatin formation in the euchromatic region (10). The expression of the epithelial Na ϩ channel is also repressed by the Dot1a (murine DOT1 alternative splicing variant a)-AF9 complex (11,12).…”

mentioning

confidence: 99%

Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

Kim

Park

et al. 2012

Journal of Biological Chemistry

117

111

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Multiple histone modifications in euchromatin promote heterochromatin formation by redundant mechanisms in Saccharomyces cerevisiae

Cited by 27 publications

References 100 publications

The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

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