Maintenance of Low Histone Ubiquitylation by Ubp10 Correlates with Telomere-Proximal Sir2 Association and Gene Silencing

Covalent histone post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation play pivotal roles in regulating many cellular processes, including transcription, response to DNA damage, and epigenetic control. Although positive-acting post-translational modifications have been studied in Saccharomyces cerevisiae, histone modifications that are associated with transcriptional repression have not been shown to occur in this yeast. Here, we provide evidence that histone sumoylation negatively regulates transcription in S. cerevisiae. We show that all four core histones are sumoylated and identify specific sites of sumoylation in histones H2A, H2B, and H4. We demonstrate that histone sumoylation sites are involved directly in transcriptional repression. Further, while histone sumoylation occurs at all loci tested throughout the genome, slightly higher levels occur proximal to telomeres. We observe a dynamic interplay between histone sumoylation and either acetylation or ubiquitylation, where sumoylation serves as a potential block to these activating modifications. These results indicate that sumoylation is the first negative histone modification to be identified in S. cerevisiae and further suggest that sumoylation may serve as a general dynamic mark to oppose transcription.

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“…4A, right). This correlation is opposite to the pattern previously observed for H2B ubiquitylation (Emre et al 2005).…”

Section: Sumoylation Is Higher At Subtelomeres Compared With More Intcontrasting

confidence: 99%

Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications

Nathan¹,

Ingvarsdottir²,

Sterner³

et al. 2006

Genes Dev.

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306

257

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“…2005) and USP7 in humans (Emre et al . 2005). Although histones H3 and H4 have been shown to undergo ubiquitylation, the function of their monoubiquitylated forms is unclear (Cao & Yan 2012), with the exception of H3 monoubiquitylated at K23 by UHRF1 as described below.…”

Section: Histone Monoubiquitylation and Transcriptional Regulationmentioning

confidence: 99%

Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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“…Two deubiquitylating enzymesUbp8 (Henry et al, 2003;Daniel et al, 2004) and Ubp10 (Emre et al, 2005;Gardner et al, 2005)-have been shown to deubiquitylate H2B at K123. The finding that other sites in H2B are ubiquitylated and that K123 can be polyubiquitylated raises the possibility that these noncanonical ubiquitylation events can also be regulated by Ubp8 and/or Ubp10.…”

Section: There Are At Least Two Distinct Types Of Polyubiquitylated H2bmentioning

confidence: 99%

“…Although only ϳ10% of steady-state H2B is monoubiquitylated (Robzyk et al, 2000), it is likely that a much larger percentage of H2B is actually ubiquitylated and that deubiquitylation is an active and crucial process (reviewed in Emre and Berger, 2004). In support of this notion, the H2B-Ub-specific protease Ubp8, which is part of the SAGA complex (Henry et al, 2003;Daniel et al, 2004), is important for gene activation (Henry et al, 2003), whereas Ubp10, which is thought to preferentially remove Ub from H2B at the telomeres (Emre et al, 2005;Gardner et al, 2005), is important for gene silencing (Kahana and Gottschling, 1999). These findings have led to a model in which cycles of H2B ubiquitylation and deubiquitylation provide directionality to different stages in the transcription process (e.g., Wyce et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Ubiquitylation of H2B (H2B-Ub) at this site participates in a variety of processes, including establishment of cell size (Hwang et al, 2003), meiosis (Robzyk et al, 2000;Yamashita et al, 2004), gene activation (Kao et al, 2004), gene silencing (Dover et al, 2002;Sun and Allis, 2002), and histone H3 methylation (Dover et al, 2002;Sun and Allis, 2002). H2B ubiquitylation is reportedly higher at active genes than at the silenced telomeres (Emre et al, 2005), and both the recruitment and activity of the H2B-ubiquitylation machinery are regulated by interactions with the transcriptional apparatus, including pol II (Xiao et al, 2005), the Paf complex (Ng et al, 2003;Wood et al, 2003b;Xiao et al, 2005), and Bur kinases (Wood et al, 2005). At active genes, H2B ubiquitylation is essential for the processive methylation of histone H3 at lysine residues K4 and K79 (Dover et al, 2002;Sun and Allis, 2002;Dehe et al, 2005;Shahbazian et al, 2005), but not K36 (Li et al, 2003;Wood et al, 2003b), and for recruitment of proteasomal ATPases to chromatin (Ezhkova and Tansey, 2004).…”

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confidence: 99%

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Polyubiquitylation of Histone H2B

Geng

Tansey

2008

MBoC

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Covalent modification of histones by ubiquitylation is a prominent epigenetic mark that features in a variety of chromatin-based events such as histone methylation, gene silencing, and repair of DNA damage. The prototypical example of histone ubiquitylation is that of histone H2B in Saccharomyces cerevisiae. In this case, attachment of ubiquitin to lysine 123 (K123) of H2B is important for regulation of both active and transcriptionally silent genes and participates in trans to signal methylation of histone H3. It is generally assumed that H2B is monoubiquitylated at K123 and that it is this single ubiquitin moiety that influences H2B function. To determine whether this assumption is correct, we have re-examined the ubiquitylation status of endogenous H2B in yeast. We find that, contrary to expectations, H2B is extensively polyubiquitylated. Polyubiquitylation of H2B appears to occur within the context of chromatin and is not associated with H2B destruction. There are at least two distinct modes of H2B polyubiquitylation: one that occurs at K123 and depends on the Rad6 -Bre1 ubiquitylation machinery and another that occurs on multiple lysine residues and is catalyzed by an uncharacterized ubiquitin ligase(s). Interestingly, these ubiquitylation events are under the influence of different combinations of ubiquitin-specific proteases, suggesting that they have distinct biological functions. These results raise the possibility that some of the biological effects of ubiquitylation of H2B are exerted via ubiquitin chains, rather than a single ubiquitin group. INTRODUCTIONOver the last decade, it has become apparent that covalent modification of histones plays a prominent role in establishing epigenetic patterns of gene control in eukaryotic cells (Ruthenburg et al., 2007). A variety of histone modifications have been described, including phosphorylation, methylation, and ubiquitylation. These modifications frequently occur in distinct, interrelated patterns, giving rise to the notion that there is a histone code that is read by the cellular machinery to set the transcriptional status of a particular piece of chromatin (Jenuwein and Allis, 2001).Interestingly, one of the first covalent histone modifications to be discovered was ubiquitylation. In their characterization of the nuclear protein "A24," Busch and colleagues (Goldknopf et al., 1975;Goldknopf and Busch, 1977) described an isopeptide linkage between lysine 119 (K119) of histone H2A and the protein that is now known as ubiquitin (Ub). Early studies (e.g., Levinger and Varshavsky, 1982) demonstrated a connection between histone ubiquitylation and the transcriptional status of chromatin, and it is now clear that histone ubiquitylation, which has been reported for H2A, H2B, H3, and H4 (Muratani and Tansey, 2003), is an important regulatory modification involved in both gene silencing (e.g., de Napoles et al., 2004;Fang et al., 2004) and activation (e.g., Kao et al., 2004). Because of the genetics available in yeast, most of what is known about the functional sign...

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Maintenance of Low Histone Ubiquitylation by Ubp10 Correlates with Telomere-Proximal Sir2 Association and Gene Silencing

Cited by 162 publications

References 55 publications

Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications

Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications

Protein monoubiquitylation: targets and diverse functions

Polyubiquitylation of Histone H2B

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