Methylation of Histone H3 by COMPASS Requires Ubiquitination of Histone H2B by Rad6

Dover, Jim; Schneider, Jessica; Tawiah-Boateng, Mary Anne; Wood, Adam; Dean, Kimberly; Johnston, Mark; Shilatifard, Ali

doi:10.1074/jbc.c200348200

Cited by 497 publications

(452 citation statements)

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“…We now know that monoubiquitination of H2B is required for H3K4 di-and trimethylation in yeast and that this crosstalk pathway is highly conserved from yeast to human [6,40,41]. Although the past several years brought about a watershed of information regarding the factors/proteins required for proper H2B monoubiquitination [6,[40][41][42][43][44][45][46][47][48], the molecular mechanism for this histone crosstalk was poorly understood. Recent studies in yeast S. cerevisiae demonstrated that monoubiquitination of histone H2B regulates COMPASS' compositional assembly, and therefore, proper H3K4 methylation [49].…”

Section: H2b Monoubiquitination Crosstalk In H3k4 Methylationmentioning

confidence: 99%

Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

Shilatifard

2008

Current Opinion in Cell Biology

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Chromosomal surfaces are ornamented with a variety of posttranslational modifications of histones, which are required for the regulation of many of the DNA-templated processes. Such histone modifications include acetylation, sumoylation, phosphorylation, ubiquitination and methylation. Histone modifications can either function by disrupting chromosomal contacts or by regulating nonhistone protein interactions with chromatin. In this review, recent findings will be discussed regarding the regulation of the implementation and physiological significance for one such histone modification, histone H3 Lysine 4 (H3K4) methylation by the yeast COMPASS and mammalian COMPASS-like complexes.All DNA-templated processes are regulated by chromatin and its posttranslational modifications. The nucleosome, which is the fundamental unit of chromatin, is composed of 146 base pairs of DNA wrapped twice around an octamer of the four core histones (H3, H4, H2A, and H2B) [1][2][3]. Structural studies demonstrated that the unstructured histone N-terminal tails protrude outward from the nucleosomes and are available for interactions with other neighboring histones or non-histone proteins. Many residues within the histone N-terminal tails and a few within the histone core can be altered by posttranslational modifications [1]. To date, there are at least five types of posttranslational modifications found on histones, these include: acetylation, phosphorylation, ubiquitination, sumoylation, and methylation [4,5]. Almost all of these modifications have been shown to be reversible, and their implementation and removal are fundamental to the regulation of a diverse set of biological processes such as replication, repair, recombination, transcription and RNA processing [4,5]. This review will focus mainly on the most recent studies of one type of histone modification, histone H3 lysine 4 (H3K4) methylation. Histone lysine methylationHistones are methylated either on their arginine and/or lysine residues [6,7]. The lysine residues are methylated on the ε-nitrogen by either the SET domain or the non-SET domain-containing lysine methyltransferases (KMTs). A large number of enzymes have been characterized which are capable of methylating specific lysine residues on histones ( Table 1). The ε-nitrogen can also be modified by lysine acetyl transferases (KATs) and methylation and acetylation of lysine are mutually exclusive. Indeed, many sites of histone methylation are also sites of acetylation.Correspondence and proofs should be sent to the following address: Ali Shilatifard, Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, Office (816) 926-4465, Email: ASH@Stowers-Institute.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable for...

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Section: H2b Monoubiquitination Crosstalk In H3k4 Methylationmentioning

confidence: 99%

Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

Shilatifard

2008

Current Opinion in Cell Biology

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“…The first breakthrough came with the identification of the budding yeast protein Bre1 [38,39], which, together with the ubiquitin-conjugating enzyme Rad6, serves as the E3 ligase in the monoubiquitylation of the yeast histone H2B on lysine 123 (K123) within transcribed chromatin [38][39][40][41]. 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].…”

Section: Monoubiquitylated Histone H2bmentioning

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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“…Yeast deleted for RAD6 or BRE1, or carrying the K123R H2B mutant, display reduced GAL gene activation (Kao et al, 2004), as well as defects in meiosis (Robzyk et al, 2000;Yamashita 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), but are nonetheless viable. Our finding that there are multiple ubiquitylation events on histone H2B raises the important point that previous analyses of the functional consequences of Rad6 -Bre1-dependent H2B ubiquitylation (at K123) have been performed within a backdrop of other H2B-ubiquitylation events, which in turn may mask effects resulting from loss of Rad6 -Bre1 ubiquitylation.…”

Section: Ubiquitylation Of Lysine 123 Of H2b Can Be Essentialmentioning

confidence: 99%

“…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).…”

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).…”

Section: Introductionmentioning

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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Methylation of Histone H3 by COMPASS Requires Ubiquitination of Histone H2B by Rad6

Cited by 497 publications

References 25 publications

Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

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

Polyubiquitylation of Histone H2B

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