Acetylation histone lysine

Kramer OH, Baus D, Knauer SK, Stein S, Jager E, Stauber RH, Grez M, Pfitzner E, Heinzel T (2006) Acetylation of Stall modulates NF-kappaB activity. Genes Dev 20(4) 473 85 Kumar BR, Swaminathan V, Banerjee S, Kundu TK (2001) p300-mediated acetylation of human transcriptional coactivator PC4 is inhibited by phosphorylation. J Biol Chem 276(20) 16804-16809 Lim JH, West KL, Rubinstein Y, Bergel M, Postnikov YV, Bustin M (2005) Chromosomal protein HMGNl enhances the acetylation of lysine 14 in histone H3. EMBO J 24(17) 3038-3048 Li M, Luo J, Brooks CL, Gu W (2002) Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277(52) 50607-50611... 

Markham D, Munro S, Soloway J, O Connor DP, La Thangue NB (2006) DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. EMBO Rep.7(2) 192-198 Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 6(11) 838-849... 

Lo WS, Trievel RC, Rojas JR, Duggan L, Hsu JY, Allis CD, Marmorstein R, Berger SL (2000) Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol Cell 5(6) 917—926... 

Methylation plays an important role in transcriptional regulation and a lesser role in signal transduction. " Histones are heavily methylated proteins. Single, double, or triple methylated lysines play an important role on histones. Lysine methylation is a more subtle transcriptional control than acetylation. Lysine methylation has come to light in another protein known as p53. p53 is a protein expressed in low levels in the cell and stabilized by posttranslational modifications including phosphorylation, acetylation, and now N-methylation. There are several C-terminal lysines on p53 that increase its stability. The addition of the methylation modifications adds complexity to p5 3 and fine-tunes its activity and ultimately suppresses tumor formation. ... 

The phenylselenocysteine has also been used successfully to chemically append analogues of methyl- or acetyl-lysine, important histone modifications that can contribute to chromatin structure and accessibility of transcriptional machinery in eukaryotes. By introducing phenylselenocysteine into the Xenopus histone H3, both acetyl-lysine and mono-, di-, and trimethyl-lysine analogues were appended to the purified unnatural amino acid-containing FI 3 protein (Figure 10). " Additionally, the H3 protein with a modification mimicking acetylation of lysine 9 can be deactylated by a histone deacetylation complex and is also a substrate for phosphorylation by Aurora B kinase. Such purified and chemically labeled histones are likely functional in nucleosomes, and preparation of specifically modified histones for comprehensive analysis of chromatin structure and accessibility is particularly suited to this chemical labeling technique. 

Acetylation is a reversible modification on proteins that can also contribute to protein localization and function. Acetylation of lysine residues in histone proteins can control the secondary structure of chromatin as well as gene expression levels from certain loci, and chromatin remodeling and its consequences in a variety of molecular and cell biological questions are intensely researched. Many other proteins undergo reversible acetylation, and the functional consequences of these modifications are poorly understood in many cases. 

Messenger RNAs for H2A.Bbd have been detected in human testis, fibroblasts and lymphocytes [77], but little is known about the amount of H2A.Bbd protein in these or other human cell types or about its presence in other species. The distribution of H2A.Bbd in chromatin was examined by expressing epitope-tagged or GFP-tagged H2A.Bbd in cultured cells. These studies revealed a striking deficiency of H2A.Bbd in the inactive X chromosome, leading to its name which stands for Histone H2A Barr-body deficient [77]. The distribution of H2A.Bbd overlapped extensively with that of H4 acetylated on lysine 12, suggesting that H2A.Bbd may preferentially associate with transcriptionally active chromatin. 

A true appreciation of the subtle and complex ways in which the nucleosome can influence gene expression, has come only recently, largely through studies of the post-translational modifications to which all histones are subject and of the enzymes that add and remove these modifications. It has been known for many years that the histone N-terminal tails are exposed on the surface of the nucleosome and that selected amino acid residues are subject to a variety of enzyme-catalyzed, post-translational modifications. These include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines ([6,7], see also chapters by Davie, and Ausio and Abbott, this volume). The locations of the histone N-terminal tails in the nucleosome and the residues that can be modified are shown in Fig. 1. 

The first indication that modification of specific tail residues were linked to chromatin functional states, came from immunostaining of Drosophila polytene chromosomes with antibodies specific for H4 acetylated at defined lysines [13]. As shown in Fig. 2A, H4 acetylated at lysine 16 (H4acK16) was found almost exclusively on the transcriptional hyperactive male X chromosome (Fig. 2). (Genes on the Drosophila male X are transcribed twice as fast as their female counterparts so as to equalize levels of X-linked gene products between XY males and XX females.) In addition, H4 lysine 12 was found to remain acetylated in centric heterochromatin, while lysines 5, 8, and 16 were all under-acetylated [13]. These observations led to the suggestion that the histone N-terminal tails constitute nucleosome surface markers that can be recognized by non-histone proteins in a modification-dependent manner to alter the functional state of chromatin [13]. 

The co-repressor KAP-1 functionally links the DNA-binding Kruppel-associated box zinc finger proteins to the NURD complex by recruiting the Mi-2a subunit. [251]. This interaction requires a tandem PHD/bromodomain motif in which the individual domains appear to act together as a functional unit. The nature of any possible acetylated lysine targets of the bromodomain remains unclear but it is not excluded that this domain could bind to an acetylated lysine in Mi-2a rather than to an acetylated histone tail. 

Histone acetyltransferases (HATs) are enzymes that acetylate specific lysine residues in histones through the transfer of an acetyl group from an acetyl-coenzymeA (AcCoA) molecule, causing profound effects on chromatin structure and assembly as well as gene transcription. HATs are found in most, if not all, eukaryotic organisms as multiprotein complexes, some HAT catalytic subunits even being shared between various complexes that display different substrate specificities based on their subunit composition [12]. Despite their name, HATs do not restrict themselves to the acetylation of histones, since these enzymes have also been shown to act on nonhistone proteins, broadening their scope of action [13]. 

Histone deacetylases (HDAGs) catalyze the removal of acetyl groups from the Ne atom of histone lysines in a nucleosomal context, ensuring the reversibility of histone acetylation. Histone deacetylation is often associated vdth transcriptional repression and silencing since it promotes chromatin higher order structures and the recruitment of silencers [34]. As other enzymes involved in chromatin... 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

The equilibrium of reversible histone lysine acetylation is maintained by histone deacetylases (H D ACs) on one hand and histone acetyltransferases on the other hand. Human histone deacetylases can be separated into four classes [15]. HDACs of class I, II and IV are zinc-dependent amidohydrolases, whereas class III HDACs, also referred to as sirtuins, have a mechanism that is dependent on NAD [16]. As histone deacetylases have been widely studied, it is not surprising that there are also a large number of assays existing that have helped to characterize modulators of these enzymes and subsequently the enzymes themselves. 

Histone acetyltransferases (H ATs) catalyze the transfer of an acetyl moiety from acetyl-CoA to the E-amino group of certain lysine residues within core histone proteins. This transferase reaction produces acetylated histones and the deacetylated cofactor CoA-SH. As HATs are important enzymes in the regulation of gene expression, there are also a number of assays available to detect acetyltransferases activity. 

Ito, K., Barnes, P.J. and Adcock, I.M. (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-lbeta-induced histone H4 acetylation on lysines 8 and 12. Molecular and Cellular Biology, 20, 6891-6903. 

Histone methylation participates in the regulation of gene expression patterns. Unlike histone acetylation, histone methylation does not alter the charge of the amino acid and hence the histone tail. There are changes in the basicity and the hydrophobicity which are relatively small when viewed at the scale of the histone but still influence the affinity of the histone tails to certain proteins, for example transcription factors, which in turn result in certain signaling events. The histone methyltransferases are usually subdivided into three classes SET domain lysine methyltransfeases, nonSET domain lysine methyltransferases and arginine methyltransferases (PRMTs). All of them utilize S-adenosylmethionine (SAM) as cosubstrate for the methylation reaction... 

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