Proteasomal ATPases Link Ubiquitylation of Histone H2B to Methylation of Histone H3

Ezhkova, Elena; Tansey, William P.

doi:10.1016/s1097-2765(04)00026-7

Cited by 190 publications

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“…Notably, H2B monoubiquitylation was subsequently found to be required for di-and trimethylation of lysine 4 and lysine 79 of histone H3 at transcribed chromatin [42][43][44][45][46][47][48]. 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].…”

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“…Thus, while carrying out its regular enzymatic activity in the DDR context, it was presumably physically and functionally detached from its regular context. In the transcription context, H2B monoubiquitylation in yeast and mammals is dependent on the early steps in transcription initiation and elongation, and the corresponding E3 ligase closely interacts with many proteins that take part in this process, some of which associate directly with RNA Pol II [41,[49][50][51][52][53][54]99,100]. It is not entirely clear how many of the proteins surrounding RNF20-RNF40 in the transcription context accompany this heterodimer to the DNA damage sites.…”

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

et al. 2011

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“…H2B ubiquitination is a prerequisite for a second modification on a different histone. Methylation of H3 at lysine residues depends on the ubiquitination of histone H2B (46). Reduced ubiquitination of H2B reduces H3 lysine-79 di-methylation and correlates with a decreased gene expression.…”

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The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

et al. 2011

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Abstract. Recent data have provided information regarding the profiles of clear cell carcinoma of the ovary (CCC) with adenine-thymine rich interactive domain 1A (ARID1A) mutations. The purpose of this review was to summarize current knowledge regarding the molecular mechanisms involved in CCC tumorigenesis and to describe the central role played by the aberrant chromatin remodeling. The present article reviews the English-language literature for biochemical studies on the ARID1A mutation and chromatin remodeling in CCC. ARID1A is responsible for directing the SWI/SNF complex to target promoters and regulates the transcription of certain genes by altering the chromatin structure around those genes. The mutation spectrum of ARID1A was enriched for C to T transitions. CCC and clear cell renal cell carcinoma (ccRCC) resemble each other pathogenetically. Dysfunction of the ARID1A protein, which occurs with VHL mutations in ccRCC, is responsible for loss of the assembly of the ARID1A-mediated histone H2B complex. Therefore, ARID1A acts as a chromatin remodeling modifier, which stimulates cell signaling that can lead to cell cycle arrest and cell death in the event of DNA damage. The dysfunction of ARID1A may result in susceptibility to CCC carcinogenesis through a defect in the repair or replication of damaged DNA. IntroductionEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide. Epidemiology calculations of lifetime risk for EOC are that 1 in 55 women is likely to develop EOC during their lifetime (1). Since EOC is more likely to be advanced stage with unfavorable tumor biology, there are serious limitations to the surgical and oncological treatment available. Therefore, it is crucial to determine the earliest possible diagnosis. Early diagnosis and surgical resection offer patients the best opportunity of excellent long-term survival. On the other hand, patients who either present with metastatic disease or develop distant relapse within 6 months after surgery and chemotherapy have a poor prognosis. Among EOC, clear cell carcinomas of the ovary (CCC) are frequently characterized by chemoresistance and recurrence, resulting in a poor prognosis (2). Since CCC are resistant to conventional cytotoxic (platinum plus taxan-based) chemotherapy, the prognosis is mostly poor (3). In the USA, the incidence of CCC is 5% of all EOC, but the incidence in Japan is reported to be over 20% of all EOC. Thus, Japanese oncologists have focused on investigating the molecular pathogenesis and treatment strategies of CCC.At present, little is known about the molecular genetic mechanisms that are involved in CCC tumorigenesis. Accumulated somatic mutations found in a subset of cancer genes are frequently noted. Such mutations include insertions/deletions (indels) and base substitutions that act as the 'driver mutations' in oncogenesis. These mutations result in the activation of proto-oncogenes (gain of function) or the inhibition of tumor suppressor genes (loss of function) during the process of carcinoge...

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“…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). 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).…”

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“…As described above, poly-Ub chains could recruit Ub-dependent chaperones to chromatin, which in turn facilitate the known functions of K123 ubiquitylation. Indeed, we have previously found that H2B ubiquitylation is required for recruitment of 19S proteasomal ATPases to chromatin (Ezhkova and Tansey, 2004) and that mutations in these ATPases result in loss of histone H3 (K4 and K79) methylation, which is itself a Rad6 -Bre1/ K123-dependent process. This finding has led us to propose that 19S proteins come to chromatin in a Ub-dependent manner and promote H3 methylation by altering local chromatin structure.…”

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Polyubiquitylation of Histone H2B

Geng

Tansey

2008

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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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Proteasomal ATPases Link Ubiquitylation of Histone H2B to Methylation of Histone H3

Cited by 190 publications

References 39 publications

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

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

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

Polyubiquitylation of Histone H2B

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