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Query: UNIPROT:P06889 (Mol)
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In Saccharomyces cerevisiae histone H2B is ubiquitylated at lysine 123 in a process requiring the E2-ubiquitin conjugase, Rad6. We have analyzed gene expression in a strain containing a variant of histone H2B with lysine 123 converted to arginine to address the mechanisms by which ubiquitylation and deubiquitylation of histone H2B affect gene expression. The SAGA complex component, Ubp8, is one of two proteases that remove the ubiquitin moiety at lysine 123. We show that changes in gene expression observed upon deletion of ubp8 are suppressed by htb1 ( K123R ), which provides genetic evidence that Ubp8 alters gene expression through deubiquitylation of histone H2B. Microarray analyses of the htb1 ( K123R ) strain show that loss of histone ubiquitylation results in a twofold or greater change in expression of approximately 1.5% of the protein coding genes with approximately 75% of these increasing. For genes in which ubiquitylation represses expression, ubiquitylation principally acts through its effects on histone methylation. In contrast, decreased expression of the CWP1 gene was not paralleled by deletions of methyltransferase components and is thus likely independent of methylation. Finally, by comparing gene expression changes in the htb1 ( K123R ) strain with those in a strain deleted for rad6, we conclude that lysine 123 affects transcription primarily because of it being a site of ubiquitylation.
Mol Genet Genomics 2007 May
PMID:The role of histone ubiquitylation and deubiquitylation in gene expression as determined by the analysis of an HTB1(K123R) Saccharomyces cerevisiae strain. 1744 2

Chromatin condensation is the most recognizable nuclear hallmark of apoptosis. Cleavage and activation of MST1 by caspases induce chromatin condensation. It was previously reported that, during apoptosis, activated MST1 induced c-Jun N-terminal kinase (JNK) activation and also phosphorylated histone H2B. However, which of these mechanisms underlies MST1's induction of chromatin condensation has yet to be clarified. Here, we report that MST1-mediated activation of JNK is both essential and sufficient for chromatin condensation. MST1 activation did not result in chromatin condensation in mitogen-activate protein kinase kinase 4 (MKK4)/MKK7 double knockout (MKK4/7 DKO) embryonic stem (ES) cells, which genetically lack the ability to activate JNK. On the other hand, constitutively active JNK was able to induce chromatin condensation in MKK4/7 DKO ES cells. In contrast, histone H2B phosphorylation did not correlate with chromatin condensation in wild-type ES cells. Finally, inhibition of JNK as well as inhibitor of caspase-activated DNase blocked chromatin condensation during Fas-mediated apoptosis of Jurkat cells. Taken together, our results indicate that caspase-mediated cleavage of MST1, followed by MST1-mediated activation of the JNK pathway, is the mechanism responsible for inducing chromatin condensation during apoptosis.
Mol Cell Biol 2007 Aug
PMID:Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis. 1754 76

Histone modifications play an important role in transcription. We previously studied histone H2B ubiquitylation on lysine 123 and subsequent deubiquitylation by SAGA-associated Ubp8. Unlike other histone modifications, both the addition and removal of ubiquitin are required for optimal transcription. Here we report that deubiquitylation of H2B is important for recruitment of a complex containing the kinase Ctk1, resulting in phosphorylation of the RNA polymerase II (Pol II) C-terminal domain (CTD), and for subsequent recruitment of the Set2 methyltransferase. We find that Ctk1 interacts with histones H2A and H2B, and that persistent H2B ubiquitylation disrupts these interactions. We further show that Ubp8 enters the GAL1 coding region through an interaction with Pol II. These findings reveal a mechanism by which H2B ubiquitylation acts as a barrier to Ctk1 association with active genes, while subsequent deubiquitylation by Ubp8 triggers Ctk1 recruitment at the appropriate point in activation.
Mol Cell 2007 Jul 20
PMID:H2B ubiquitylation acts as a barrier to Ctk1 nucleosomal recruitment prior to removal by Ubp8 within a SAGA-related complex. 1764 76

Histone N-terminal domains play critical roles in regulating chromatin structure and gene transcription. Relatively little is known, however, about the role of the histone H2A N-terminal domain in transcription regulation. We have used DNA microarrays to characterize the changes in genome-wide expression caused by mutations in the N-terminal domain of histone H2A. Our results indicate that the N-terminal domain of histone H2A functions primarily to repress the transcription of a large subset of the Saccharomyces cerevisiae genome and that most of the H2A-repressed genes are also repressed by the histone H2B N-terminal domain. Using the histone H2A microarray data, we selected three reporter genes (BNA1, BNA2, and GCY1), which we subsequently used to map regions in the H2A N-terminal domain responsible for this transcriptional repression. These studies revealed that a small subdomain in the H2A N-terminal tail, comprised of residues 16 to 20, is required for the transcriptional repression of these reporter genes. Deletion of either the entire histone H2A N-terminal domain or just this small subdomain imparts sensitivity to UV irradiation. Finally, we show that two residues in this H2A subdomain, serine-17 and arginine-18, are specifically required for the transcriptional repression of the BNA2 reporter gene.
Mol Cell Biol 2007 Nov
PMID:Regulation of gene transcription by the histone H2A N-terminal domain. 1772 83

Nitric oxide (NO) is a transmitter for intracellular and extracellular signals. It is known that nitric oxide suppresses DNA replication and expression of genes responsible for cell growth and proliferation. In this study we investigated the effect of NO on histone H2B gene expression in human and murine cell lines. We have shown that treatment of cells with chemical NO donors leads to decreasing the histone H2B mRNA level. Using luciferase assay with reporter gene regulated by H2B gene promoter, we showed that NO reduced the reporter gene activity and mRNA level simultaneously. From these data we conclude that NO negatively regulates histone H2B transcription. We believe the affect of nitric acid on the transcription of histone gene plays important role for NO-induced cytostatic effects.
Mol Biol (Mosk)
PMID:[The role of nitric oxide in the transcription of histone gene]. 1793 82

Polycomb genes encode critical regulators of both normal stem cells and cancer stem cells. A gene signature that includes Polycomb genes and additional genes coregulated with Polycomb genes was recently identified. The expression of this signature has been reported to identify tumors with the cancer stem cell phenotypes of aggressive growth, metastasis, and therapy resistance. Most members of this 11 gene signature encode proteins with well-defined roles in human cancer. However, the function of the signature member USP22 remains unknown. We report that USP22 is a previously uncharacterized subunit of the human SAGA transcriptional cofactor complex. Within SAGA, USP22 deubiquitylates histone H2B. Furthermore, USP22 is recruited to specific genes by activators such as the Myc oncoprotein, where it is required for transcription. In support of a functional role within the Polycomb/cancer stem cell signature, USP22 is required for appropriate progression through the cell cycle.
Mol Cell 2008 Jan 18
PMID:The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. 1824 9

Dual-color fluorescent cells, with one color in the nucleus and the other in the cytoplasm, enable real-time nuclear-cytoplasmic dynamics to be visualized in living cells in vivo as well as in vitro. To obtain the dual-color cells, red fluorescent protein (RFP) is expressed in the cytoplasm of cancer cells, and green fluorescent protein (GFP) linked to histone H2B is expressed in the nucleus. Nuclear GFP expression allows visualization of nuclear dynamics, whereas simultaneous cytoplasmic RFP expression allows visualization of nuclear-cytoplasmic ratios as well as simultaneous cell and nuclear shape changes. This methodology has allowed us to show that the cells and nuclei of cancer cells in the capillaries elongate to fit the width of these vessels. The average length of the major axis of the cancer cells in the capillaries increased to approximately four times their normal length. The nuclei increased their length 1.6 times. Cancer cells in capillaries over 8 microm in diameter were shown to migrate at up to 48.3 microm/h. With the use of dual-color fluorescent cells and the Olympus OV100, a highly sensitive whole-mouse imaging system with both macrooptics and microoptics, it is possible to achieve subcellular real-time imaging of cancer cell trafficking in live mice. Extravasation can also be imaged in real time. Dual-color imaging showed that cytoplasmic processes of cancer cells exited the vessels first, with nuclei following along the cytoplasmic projections. Dual-color in vivo cellular imaging was also used to visualize trafficking, nuclear-cytoplasmic dynamics, and the viability of cancer cells after their injection into the portal vein of mice.
Methods Mol Biol 2007
PMID:Subcellular imaging of cancer cells in live mice. 1828 42

Whereas mono-, di- and trimethylation states of lysines on histones typically have specific functions, no specific functions have been attributed so far to the different methylation states of histone H3 Lysine 79 (H3K79) generated by Dot1. Here we show that Dot1, in contrast to other known histone methyltransferases, introduces multiple methyl groups via a nonprocessive mechanism. The kinetic mechanism implies that the H3K79 methylation states cannot be generated independently, suggesting functional redundancy. Indeed, gene silencing in yeast, which is dependent on Dot1, relied on global H3K79 methylation levels and not on one specific methylation state. Furthermore, our findings suggest that histone H2B ubiquitination affects H3K79 trimethylation by enhancing synthesis of all H3K79 methylation states. Our results suggest that multiple methylation of H3K79 leads to a binary code, which is expected to limit the possibilities for regulation by putative demethylases or binding proteins.
Nat Struct Mol Biol 2008 Jun
PMID:Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. 1852 63

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.
Mol Biol Cell 2008 Sep
PMID:Polyubiquitylation of histone H2B. 1856 93

In this issue of Molecular Cell, Fleming et al. (2008) show that histone H2B ubiquitylation and FACT function interdependently to facilitate nucleosome reassembly during transcription elongation, thereby demonstrating that histone posttranslational modifications can provide important but transient transcriptional signaling cues.
Mol Cell 2008 Jul 11
PMID:Just the FACTs: histone H2B ubiquitylation and nucleosome dynamics. 1861 47


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