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David C Allis - One of the best experts on this subject based on the ideXlab platform.
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ubiquitylation of Histone H2B controls rna polymerase ii transcription elongation independently of Histone h3 methylation
Genes & Development, 2007Co-Authors: Jason C Tanny, Hediye Erdjumentbromage, Paul Tempst, David C AllisAbstract:Transcription by RNA polymerase II (polII) is accompanied by dramatic changes in chromatin structure. Numerous enzymatic activities contribute to these changes, including ATP-dependent nucleosome remodeling enzymes and Histone modifying enzymes. Recent studies in budding yeast document a Histone modification pathway associated with polII transcription, whereby ubiquitylation of Histone H2B leads to methylation of Histone H3 on specific lysine residues. Although this series of events appears to be highly conserved among eukaryotes, its mechanistic function in transcription is unknown. Here we document a significant functional divergence between ubiquitylation of H2B and methylation of Lys 4 on Histone H3 in the fission yeast Schizosaccharomyces pombe. Loss of H2B ubiquitylation results in defects in cell growth, septation, and nuclear structure, phenotypes not observed in cells lacking H3 Lys 4 methylation. Consistent with these results, gene expression microarray analysis reveals a greater role for H2B ubiquitylation in gene regulation than for H3 Lys 4 methylation. Chromatin immunoprecipitation (ChIP) experiments demonstrate that loss of H2B ubiquitylation alters the distribution of polII and Histones in gene coding regions. We propose that ubiquitylation of H2B impacts transcription elongation and nuclear architecture through its effects on chromatin dynamics.
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Histone H2B deacetylation at lysine 11 is required for yeast apoptosis induced by phosphorylation of H2B at serine 10
Molecular Cell, 2006Co-Authors: Sunghee Ahn, Michael Grunstein, Robert L Diaz, David C AllisAbstract:Chromatin alterations, induced by covalent Histone modifications, mediate a wide range of DNA-templated processes, including apoptosis. Apoptotic chromatin condensation has been causally linked to the phosphorylation of Histone H2B (serine 14 in human; serine 10 in yeast, H2BS10ph) in human and yeast cells. Here, we extend these studies by demonstrating a unidirectional, crosstalk pathway between H2BS10 phosphorylation and lysine 11 acetylation (H2BK11ac) in yeast. We demonstrate that the H2BK11 acetyl mark, which exists in growing yeast, is removed upon H(2)O(2) treatment but before H2BS10ph occurs, in a unidirectional fashion. H2B K11Q mutants are resistant to cell death elicited by H(2)O(2), while H2B K11R mutants that mimic deacetylation promote cell death. Our results suggest that Hos3 HDAC deacetylates H2BK11ac, which in turn mediates H2BS10ph by Ste20 kinase. Together, these studies underscore a concerted series of enzyme reactions governing Histone modifications that promote a switch from cell proliferation to cell death.
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sterile 20 kinase phosphorylates Histone H2B at serine 10 during hydrogen peroxide induced apoptosis in s cerevisiae
Cell, 2005Co-Authors: David C Allis, Wang L Cheung, Sunghee Ahn, Jeryuan Hsu, Robert L Diaz, Mitchell M SmithAbstract:Abstract Apoptosis is a highly coordinated cell suicide mechanism in vertebrates. Phosphorylation of serine 14 of Histone H2B, catalyzed by Mst1 kinase, has been linked to chromatin compaction during apoptosis. We extend these results to unicellular eukaryotes by demonstrating that H2B is specifically phosphorylated at serine 10 (S10) in a hydrogen peroxide-induced cell death pathway in S. cerevisiae . H2B S10A mutants are resistant to cell death elicited by H 2 O 2 while H2B S10E phospho-site mimics promote cell death and induce the "constitutive" formation of condensed chromatin. Ste20 kinase, a yeast homolog of mammalian Mst1 kinase, translocates into the nucleus in a caspase-independent fashion and directly phosphorylates H2B at S10. Conservation of targeted H2B phosphorylation and the enzyme system responsible for the process point to an ancient mechanism of chromatin remodeling that likely plays an important role in governing cellular homeostasis in a wide range of organisms.
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phosphorylation of Histone H2B at dna double strand breaks
Journal of Experimental Medicine, 2004Co-Authors: Oscar Fernandezcapetillo, David C Allis, Andre NussenzweigAbstract:Posttranslational modifications of Histone tails regulate numerous biological processes including transcription, DNA repair, and apoptosis. Although recent studies suggest that structural alterations in chromatin are critical for triggering the DNA damage response, very little is known about the nature of DNA damage-induced chromatin perturbations. Here we show that the serine 14 residue in the NH2-terminal tail of Histone H2B is rapidly phosphorylated at sites of DNA double-strand breaks. At late time points after irradiation, the phosphorylated form of H2B, H2B-Ser14P, accumulates into irradiation-induced foci. H2B-Ser14P foci formation is not associated with the apoptotic phosphorylation of H2B but is strictly dependent on the phosphorylated isoform of H2AX. Our results broaden the spectrum of Histone modifications that constitute the DNA damage “Histone code” and suggest a model for the underlying chromatin structure within damage-induced foci.
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deubiquitination of Histone H2B by a yeast acetyltransferase complex regulates transcription
Journal of Biological Chemistry, 2004Co-Authors: Jeremy A Daniel, David C Allis, Michael S Torok, David Schieltz, John R Yates, Patrick A GrantAbstract:Post-translational modifications of the Histone protein components of eukaryotic chromatin play an important role in the regulation of chromatin structure and gene expression (1). Given the requirement of Rad6/Bre1-dependent ubiquitination of Histone H2B for H3 dimethylation (at lysines 4 and 79) and gene silencing (2-7), removal of ubiquitin from H2B may have a significant regulatory effect on transcription. Here we show that a putative deubiquitinating enzyme, Ubp8, is a structurally nonessential component of both the Spt-Ada-Gcn5-acetyltransferase (SAGA) and SAGA-like (SLIK) Histone acetyltransferase (HAT) complexes in yeast. Disruption of this gene dramatically increases the cellular level of ubiquitinated-H2B, and SAGA and SLIK are shown to have H2B deubiquitinase activity. These findings demonstrate, for the first time, how the ubiquitin moiety can be removed from Histone H2B in a regulated fashion. Ubp8 is required for full expression of the SAGA- and SLIK-dependent gene GAL10 and is recruited to the upstream activation sequence (UAS) of this gene under activating conditions, while Rad6 dissociates. Furthermore, trimethylation of H3 at lysine 4 within the UAS increases significantly under activating conditions, and remarkably, Ubp8 is shown to have a role in regulating the methylation status of this residue. Collectively, these data suggest that the SAGA and SLIK HAT complexes can regulate an integrated set of multiple Histone modifications, counteracting repressive effects that alter chromatin and regulate gene expression.
Masaharu Kogure - One of the best experts on this subject based on the ideXlab platform.
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the oncogenic polycomb Histone methyltransferase ezh2 methylates lysine 120 on Histone H2B and competes ubiquitination
Neoplasia, 2013Co-Authors: Masaharu Kogure, Masashi Takawa, Vassiliki Saloura, Kenbun Sone, Lianhua Piao, Koji Ueda, Reem Ibrahim, Tatsuhiko Tsunoda, Masanori SugiyamaAbstract:The Histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.
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the oncogenic polycomb Histone methyltransferase ezh2 methylates lysine 120 on Histone H2B and
2013Co-Authors: Masaharu Kogure, Masashi Takawa, Vassiliki Saloura, Kenbun Sone, Lianhua Piao, Koji Ueda, Reem Ibrahim, Tatsuhiko Tsunoda, Masanori Sugiyama, Yutaka AtomiAbstract:The Histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation–Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.
Yusuke Nakamura - One of the best experts on this subject based on the ideXlab platform.
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abstract 5156 the oncogenic polycomb Histone methyltransferase ezh2 methylates lysine 120 on Histone H2B and competes ubiquitination in human cancer
Cancer Research, 2014Co-Authors: Ryuji Hamamoto, Yusuke NakamuraAbstract:The Histone methyltransferase EZH2 is known to be a polycomb protein homologus to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In this study, we demonstrated that EZH2 has the function to mono-methylated lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key post-translational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent ChIP-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis. Citation Format: Ryuji Hamamoto, Yusuke Nakamura. The oncogenic polycomb Histone methyltransferase EZH2 methylates lysine 120 on Histone H2B and competes ubiquitination in human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5156. doi:10.1158/1538-7445.AM2014-5156
Ali Shilatifard - One of the best experts on this subject based on the ideXlab platform.
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Histone H2B monoubiquitination functions cooperatively with fact to regulate elongation by rna polymerase ii
Cell, 2006Co-Authors: Rushad Pavri, Subhrangsu S Mandal, Ali Shilatifard, Ing Zhu, Patrick Troje, Danny ReinbergAbstract:Over the past years, a large number of Histone posttranslational modifications have been described, some of which function to attain a repressed chromatin structure, while others facilitate activation by allowing access of regulators to DNA. Histone H2B monoubiquitination is a mark associated with transcriptional activity. Using a highly reconstituted chromatin-transcription system incorporating the inducible RARβ2 promoter, we find that the establishment of H2B monoubiquitination by RNF20/40 and UbcH6 is dependent on the transcription elongation regulator complex PAF, the Histone chaperone FACT, and transcription. H2B monoubiquitination facilitates FACT function, thereby stimulating transcript elongation and the generation of longer transcripts. These in vitro analyses and corroborating in vivo experiments demonstrate that elongation by RNA polymerase II through the nucleosomal barrier is minimally dependent upon (1) FACT and (2) the recruitment of PAF and the H2B monoubiquitination machinery.
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the bur1 bur2 complex is required for Histone H2B monoubiquitination by rad6 bre1 and Histone methylation by compass
Molecular Cell, 2005Co-Authors: Adam Wood, Jessica Schneider, Jim Dover, Mark Johnston, Ali ShilatifardAbstract:To date, several classes of enzymes have been shown to affect transcription by catalyzing the modifications of nucleosomes via methylation. Employing our global proteomic screen, GPS, we have determined that the loss of Bur2, a component of the Bur1/Bur2 cyclin-dependent protein kinase, results in a decrease in Histone H3(K4) methylation catalyzed by COMPASS. Furthermore, Bur1/Bur2 is required for Histone H2B monoubiquitination by Rad6/Bre1. The effect on Histone monoubiquitination and methylation is the result of defective Bur1/Bur2-mediated phosphorylation of Rad6 on its serine residue 120 and proper recruitment of the Paf1 complex to chromatin. We have also demonstrated that serine 120 of Rad6 is required for Histone H2B monoubiquitination and the regulation of gene expression in vivo. Our results identify in vivo substrates for Bur1/Bur2, thus linking its role to transcriptional elongation and demonstrating a potential activation mechanism for Histone H2B monoubiquitination by the Rad6/Bre1 complex.
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transcriptional activation via sequential Histone H2B ubiquitylation and deubiquitylation mediated by saga associated ubp8
Genes & Development, 2003Co-Authors: Karl W Henry, Anastasia Wyce, Laura J Duggan, N Tolga C Emre, Chengfu Kao, Lorraine Pillus, Ali Shilatifard, Mary Ann Osley, Shelley L BergerAbstract:Gene activation and repression regulated by acetylation and deacetylation represent a paradigm for the function of Histone modifications. We provide evidence that, in contrast, Histone H2B monoubiquitylation and its deubiquitylation are both involved in gene activation. Substitution of the H2B ubiquitylation site at Lys 123 (K123) lowered transcription of certain genes regulated by the acetylation complex SAGA. Gene-associated H2B ubiquitylation was transient, increasing early during activation, and then decreasing coincident with significant RNA accumulation. We show that Ubp8, a component of the SAGA acetylation complex, is required for SAGA-mediated deubiquitylation of Histone H2B in vitro. Loss of Ubp8 in vivo increased both gene-associated and overall cellular levels of ubiquitylated H2B. Deletion of Ubp8 lowered transcription of SAGA-regulated genes, and the severity of this defect was exacerbated by codeletion of the Gcn5 acetyltransferase within SAGA. In addition, disruption of either ubiquitylation or Ubp8-mediated deubiquitylation of H2B resulted in altered levels of gene-associated H3 Lys 4 methylation and Lys 36 methylation, which have both been linked to transcription. These results suggest that the Histone H2B ubiquitylation state is dynamic during transcription, and that the sequence of Histone modifications helps to control transcription.
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methylation of Histone h3 by compass requires ubiquitination of Histone H2B by rad6
Journal of Biological Chemistry, 2002Co-Authors: Jim Dover, Adam Wood, Jessica Schneider, Mark Johnston, Mary Anne Tawiahboateng, Kimberly Dean, Ali ShilatifardAbstract:Abstract The DNA of eukaryotes is wrapped around nucleosomes and packaged into chromatin. Covalent modifications of the Histone proteins that comprise the nucleosome alter chromatin structure and have major effects on gene expression. Methylation of lysine 4 of Histone H3 by COMPASS is required for silencing of genes located near chromosome telomeres and within the rDNA (Krogan, N. J, Dover, J., Khorrami, S., Greenblatt, J. F., Schneider, J., Johnston, M., and Shilatifard, A. (2002) J. Biol. Chem. 277, 10753–10755; Briggs, S. D., Bryk, M., Strahl, B. D., Cheung, W. L., Davie, J. K., Dent, S. Y., Winston, F., and Allis, C. D. (2001) Genes. Dev. 15, 3286–3295). To learn about the mechanism of Histone methylation, we surveyed the genome of the yeast Saccharomyces cerevisiae for genes necessary for this process. By analyzing ∼4800 mutant strains, each deleted for a different non-essential gene, we discovered that the ubiquitin-conjugating enzyme Rad6 is required for methylation of lysine 4 of Histone H3. Ubiquitination of Histone H2B on lysine 123 is the signal for the methylation of Histone H3, which leads to silencing of genes located near telomeres.
Masanori Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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the oncogenic polycomb Histone methyltransferase ezh2 methylates lysine 120 on Histone H2B and competes ubiquitination
Neoplasia, 2013Co-Authors: Masaharu Kogure, Masashi Takawa, Vassiliki Saloura, Kenbun Sone, Lianhua Piao, Koji Ueda, Reem Ibrahim, Tatsuhiko Tsunoda, Masanori SugiyamaAbstract:The Histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.
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the oncogenic polycomb Histone methyltransferase ezh2 methylates lysine 120 on Histone H2B and
2013Co-Authors: Masaharu Kogure, Masashi Takawa, Vassiliki Saloura, Kenbun Sone, Lianhua Piao, Koji Ueda, Reem Ibrahim, Tatsuhiko Tsunoda, Masanori Sugiyama, Yutaka AtomiAbstract:The Histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation–Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.