Monoubiquitination of Human Histone H2B: The Factors Involved and Their Roles in HOX Gene Regulation

Zhu, Bing; Zheng, Yong Hui; Pham, Anh Dung; Mandal, Subhrangsu S.; Erdjument‐Bromage, Hediye; Tempst, Paul; Reinberg, Danny

doi:10.1016/j.molcel.2005.09.025

Cited by 459 publications

(478 citation statements)

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“…Overexpression of HOX genes is associated with acute myeloid leukemia and promotes leukemogenesis (Scholl et al, 2007). Overexpression of hBre1 triggers robust up-regulation of many Hox genes, whereas RNA interference knocking down of hBre1 specifically down-regulates the same set of Hox genes (Zhu et al, 2005). This report suggests that hBre1 possesses proto-oncogenic activity, which fits with our observation that depletion of hBre1 suppresses MCF7 cell proliferation by enhancing p42 tumor suppressor expression, leading to down-regulation of E2F-1 promoter activity ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, PAF complex is also required for H2B ubiquitination (Ng et al, 2003;Wood et al, 2003b). In humans, the homologue of yeast Bre1 (RNF20), designated as hBre1, acts as an E3 ligase for H2B and promotes its ubiquitination at K120, the equivalent of yeast H2B K123 (Kim et al, 2005;Zhu et al, 2005). Moreover, it has a coactivator function in activator-dependent transcription of several genes.…”

Section: Introductionmentioning

confidence: 99%

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Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Liu¹,

Oh²,

Okada³

et al. 2009

MBoC

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Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation. INTRODUCTIONIn yeast, histone H2B K123 monoubiquitination is regulated by the E3 ligase Bre1 and E2-conjugating enzyme RAD6 (Robzyk et al., 2000;Hwang et al., 2003;Wood et al., 2003a). This process is a prerequisite for the subsequent histone H3-K4 and K79 methylation (Sun and Allis, 2002;Wood et al., 2003b), which marks actively transcribed genes (SantosRosa et al., 2002). Additionally, PAF complex is also required for H2B ubiquitination (Ng et al., 2003;Wood et al., 2003b). In humans, the homologue of yeast Bre1 (RNF20), designated as hBre1, acts as an E3 ligase for H2B and promotes its ubiquitination at K120, the equivalent of yeast H2B K123 (Kim et al., 2005;Zhu et al., 2005). Moreover, it has a coactivator function in activator-dependent transcription of several genes. Interestingly, hBre1 directly binds p53 and is recruited to the MDM2 promoter, regulating p53-responsive gene transcription in a p53-dependent manner. Overexpression and depletion of hBre1 increases and decreases global H2B ubiquitination, respectively. By contrast, ectopic hRAD6A and hRAD6B, human homologues of yRAD6, do not affect H2B ubiquitination or H3 methylation, suggesting that hRAD6 proteins are not cognate E2 enzymes for hBre1 (Kim et al., 2005). In addition to transcriptional coactivation of specific genes (Osley, 2004), Bre1 in Drosophila is required for Notch signaling and histone modification (Bray et al., 2005).Ebp1 was originally identified as an ErbB3 receptor-binding protein , and it is the human homologue of a previously identified cell cycle-regulated mouse protein p38-2G4 (Radomski and Jost, 1995). PA2G4 gene encodes two Ebp1 isoforms, p48 and p42, which differentially regulate PC12 cell survival and differentiation Liu et al., 2006). P48 is 54 amino acids longer than p42 at its N terminus. The longer form p48 localizes in both the cytoplasm and the nucleolus and suppresses apoptosis, whereas the shorter form p42 predominantly resides in the cytoplasm and promotes cell differentiation . Ebp1 binds the ribosome and double-st...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Liu¹,

Oh²,

Okada³

et al. 2009

MBoC

View full text Add to dashboard Cite

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“…This pathway is conserved from yeast to mammals, and is dependent on a host of additional proteins that converge at the elongating RNA Pol II [41,[49][50][51][52][53][54]. Subsequently, the mammalian orthologs of the yeast Bre1, RNF20 and RNF40, were identified [55,56]. These two proteins form a tight heterodimer that acts as the major E3 ligase responsible for histone H2B monoubiquitylation on K120 in mammalian cells.…”

Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

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“…H2A and H2B have been reported to possess acetylation (H2A: K5, K9 and H2B: K5, K12, K15, K20), phosphorylation (H2A: S1 and H2B: S10), monomethylation (H2A: K15 and H2B: K5, K43) and ubiquitination (H2A: K119 and H2B: K120/K123) [1,14,16,[36][37][38][39][40]. Thus the unambiguous assignment of the species in these profiles is complicated by possible presence of these modifications along with the variants.…”

Section: Core Histone Profilesmentioning

confidence: 99%

Liquid chromatography mass spectrometry profiling of histones

Jacob

Amunugama

et al. 2007

Journal of Chromatography B

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Here we describe the use of reverse-phase liquid chromatography mass spectrometry (RP-LC-MS) to simultaneously characterize variants and post-translationally modified isoforms for each histone. The analysis of intact proteins significantly reduces the time of sample preparation and simplifies data interpretation. LC-MS analysis and peptide mass mapping have previously been applied to identify histone proteins and to characterize their post-translational modifications. However, these studies provided limited characterization of both linker histones and core histones. The current LC-MS analysis allows for the simultaneous observation of all histone PTMs and variants (both replacement and bulk histones) without further enrichment, which will be valuable in comparative studies. Protein identities were verified by the analysis of histone H2A species using RPLC fractionation, AU-PAGE separation and nano-LC-MS/MS.

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Monoubiquitination of Human Histone H2B: The Factors Involved and Their Roles in HOX Gene Regulation

Cited by 459 publications

References 55 publications

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

Liquid chromatography mass spectrometry profiling of histones

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