Lysine acetylation - Semantic Scholar

© The Authors Journal compilation © 2012 Biochemical Society Essays Biochem. (2012) 52, 1–12: doi: 10.1042/BSE0520001

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Lysine acetylation: enzymes, bromodomains and links to different diseases Linya You*1, Jianyun Nie*†1, Wei-Jian Sun‡, Zhi-Qiang Zheng‡ and Xiang-Jiao Yang*2 *The

Rosalind & Morris Goodman Cancer Research Center, McGill University and Department of Medicine, McGill University Health Center, Montréal, Québec, Canada, H3A 1A3, †The 3rd Affiliated Hospital, Kunming Medical College, Kunming, Yunnan, China, and ‡The 2nd Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China

Abstract Lysine acetylation refers to transfer of the acetyl moiety from acetyl-CoA to the ε-amino group of a lysine residue on a protein. This has recently emerged as a major covalent modification and interplays with other modifications, such as phosphorylation, methylation, ubiquitination (addition of a small protein called ubiquitin) and SUMOylation [addition of a ubiquitin-like protein known as SUMO (small ubiquitin-related modifier)], to form multisite modification programmes for cellular regulation in diverse organisms. This modification is post-translational (i.e. after synthesis of a protein) and reversible, with its level being dynamically balanced by two groups of enzymes known as lysine acetyltransferases and deacetylases. The acetyltransferases belong to three major families, whereas deacetylases have been divided into the classical and sirtuin 1These 2To

authors contributed equally. whom correspondence should be addressed (email [email protected]). 1

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Essays in Biochemistry volume 52 2012

[Sir-tu-in, for Sir2 (silent information regulator 2)-like protein; named after the yeast protein Sir2] families. In addition to these enzymes, proteins containing the bromodomain, a protein module named after the fly protein Brahma (God of creation in Hindu), are relevant to lysine acetylation biology due to their ability to recognize acetyl-lysine-containing peptides. Importantly, recent studies have made intimate links between these three different groups of proteins to different pathological conditions. In this chapter, we provide a brief overview of these proteins and emphasize their direct links to related human diseases.

Introduction In various organisms, including humans, biological regulation is crucial in response to a constantly changing environment. Such regulation occurs at the organismal, cellular and molecular levels. One type of molecular regulation involves modification of pre-existing proteins by covalent addition or removal of chemical groups from the side chains of amino acids on the proteins and is thus known as PTM (post-translational modification). There are numerous kinds of PTM, and lysine acetylation is one of them. Lysine acetylation adds an acetyl group to the side chain of a lysine residue (Figure 1) and is dynamic and reversible. This type of regulation sounds very basic, but is of direct relevance to human health, various diseases and the action of different medicines that patients take every day. Moreover, such regulation is being actively used as an important target for developing novel therapeutics. Lysine acetylation was first discovered in the 1960s on histone proteins [1], integral components of chromatin that package and fold DNA into higher-order chromatin fibres in eukaryotic cells [2]. Known as crucial and dynamic components of gene transcriptional regulation machinery, histones undergo an elaborate series of PTMs, including acetylation, phosphorylation, methylation, ubiquitination and SUMOylation [3]. Of these modifications, acetylation was one of the first few that were discovered and studied [4]. From the initial discovery of histone acetylation over four decades ago to the recent revelation of acetyl-lysine residues in thousands of proteins, roles of lysine acetylation have expanded from maintaining the epigenome (the sequence or pattern of modification and organization of chromatin) in gene regulation and other chromatin-templated processes, to diverse cellular processes such as cytoskeleton dynamics, autophagy, membrane receptor signalling, kinase regulation, RNA processing and metabolic control [5]. The recent exciting discovery of lysine acetylomes (a collection of acetylated proteins) in diverse organisms from bacteria to yeast, Drosophila, mice and humans not only suggests that this modification is an abundant and conserved PTM [5,6], but also reveals rapid expansion of this modification during evolution. The levels of lysine acetylation in vivo are tightly controlled by opposing actions of KATs (lysine acetyltransferases) and KDACs (lysine deacetylases) (Figure 1). Since the initial identification of these enzymes in the mid-1990s, a clear picture about these enzymes has emerged. In addition, the bromodomain © The Authors Journal compilation © 2012 Biochemical Society

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Figure 1. Schematic diagram illustrating reversible acetylation and deacetylation (A) Lysine acetylation (KAT) is responsible for transferring the acetyl moiety (in red) from acetyl-CoA to the ε-group of a lysine residue, whereas an Rpd3/Hda1 family member removes the acetyl group from acetyl-lysine, releasing acetate. The activity of Rpd3/Hda1 deacetylases is Zn2+-dependent. (B) Compared with Rpd3/Hda1 deacetylases, the NAD+-dependent deacetylases, sirtuins, utilize a different catalytic mechanism. Although not discussed in the present chapter, these acetyltransferases and deacetylases may also act upon acetylation-like modifications, such as propionylation, malonylation, succinylation and crotonylation [58,59]. This cartoon was adapted, with permission, from Kim, G.W. and Yang, X.J. (2011) Comprehensive lysine acetylomes emerging from bacteria to humans. Trends Biochem. Sci. 36, 211–220. © 2011 Elsevier.

family of proteins has been shown to recognize acetyl-lysine-containing motifs. These three large families of proteins have been the favoured subject of numerous reviews and several books. To appreciate the clinical relevance of the knowledge that scientists have gained from related fundamental research, in the present chapter we provide an overview of these proteins and emphasize the direct links to various human diseases. This, hopefully, could shed light on how fundamental basic research has paved the way for uncovering and understanding clinically relevant discoveries.

Three major families of KATs Since the first KATs were identified in the mid-1990s [7,8], various mammalian proteins have been discovered to possess such enzymatic activity. On the basis of sequence homology, these proteins can be separated into three major © The Authors Journal compilation © 2012 Biochemical Society

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families: GNAT [GCN5 (general control of amino acid synthesis 5)-related N-acetyltransferase] superfamily, p300 (E1A-associated protein of 300 kDa)/ CBP [CREB (cAMP-response-element-binding protein)-binding protein] group, and the MYST {MOZ (monocytic leukaemic zinc-finger protein), Ybf2/Sas3, Sas2 and TIP60 [Tat (transactivator of transcription)-interactive protein 60 kDa]} family [9,10]. A systematic nomenclature system has been proposed [11], but some new members of the GNAT family need to be inducted into the system. GNATs Among the three families, GNATs form the largest group [9]. Members of this group include HAT (histone acetyltransferase) 1, GCN5 (general control of amino acid synthesis 5), PCAF (p300/CBP-associated factor, a paralogue of GCN5), ELP3 (elongation protein 3), CDY (chromodomain on chromosome Y) protein, Eco1 (establishment of cohesion 1), ESCO1 (establishment of cohesion 1 homologue 1), ESCO2 (a paralogue of ESCO1), ATAC2 (ADA-two-A containing 2) [12–14], and MEC17 (mechanosensory abnormal 17) [15,16]. This group also contains a bacterial KAT, PAT (protein acetyltransferase), which widens the range from bacteria to humans [17]. p300/CBP p300 and CBP do not share any sequence similarity to GNATs, and are conserved from the worm to humans, although there is only one p300/CBP-related protein in lower organisms such as the worm and fly [18]. Interestingly, even in plants, there is a protein with a domain highly homologous with the acetyltransferase domains of p300 and CBP [18]. p300 was initially identified as a protein associated with adenovirus E1A [18], whereas the closely related paralogue CBP was identified independently as a co-activator binding to the protein kinase A-phosphorylated form of CREB [18]. Human CBP and p300 are considered to be sequence and functional homologues at the molecular level with an N-terminal nuclear-receptor-binding domain, three cysteine/histidine-rich fingers, a phospho-CREB-interacting module, a bromodomain, an acetyltransferase core and a glutamine-rich domain [10]. However, p300 and CBP have distinct functions in vivo [18]. MYST proteins At the sequence level, MYST proteins display similarity to GNATs at an essential acetyl-CoA-binding motif [19,20]. As indicated above, p300 and CBP lack such a sequence motif. Moreover, like the GNAT family, the MYST family has members in all eukaryotes. In humans, there are five members, hMOF [human orthologue of fly Mof (male absent on first)], TIP60, HBO1 (HAT bound to Orc1), MOZ and MORF (MOZ-related factor) [21]. In addition to the KAT nomenclature system [11], MOF, HBO1, MOZ and MORF are also known as MYST1, 2, 3 and 4 respectively. As the fifth member of the human MYST family, TIP60 is part of a large complex containing over ten proteins, whereas HBO1, MOZ and MORF © The Authors Journal compilation © 2012 Biochemical Society

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are catalytic subunits of tetrameric complexes [21,22]. MOF is the catalytic subunit of two distinct multiprotein complexes [23,24], reinforcing the idea that these KATs tend to form multisubunit complexes as functional units in vivo.

Direct links of KATs to human diseases The KAT activities in the three families were discovered in the chronological order of GNATs, p300/CBP and MYST proteins but, as described below, direct links to human diseases have been made in a rather different sequence: p300/ CBP, MYST proteins and GNATs. p300/CBP The very first link of KATs to human diseases was made in 1995, right before the first KATs were identified. Mutations of the CBP gene were identified in patients with Rubinstein–Taybi syndrome [25]. This is an inheritable genetic disorder with characteristic features such as facial abnormalities, broad thumbs, broad big toes and mental retardation. In addition, patients have a higher tendency of forming neoplasms, indicating the importance of CBP in different developmental processes, as well as in cancer suppression. Consistent with its high sequence similarity to CBP, p300 was subsequently linked to this syndrome. One year after its mutations were linked to Rubinstein–Taybi syndrome, the CBP gene was found to be rearranged in monocytic leukaemic patients carrying a recurrent translocation between chromosomes 8 and 16 [19]. Subsequently, this gene was shown to be altered in therapy-related acute myeloid leukaemia, and the p300 gene was discovered to be mutated in leukaemia and other types of cancer (reviewed in [10]). More recent studies have revealed a recurrent translocation of bi-allelic somatic mutations of p300 in gastric and colon cancers, somatic mutations of CBP in relapsed acute lymphoblastic leukaemia [26] and inactivating mutations of CBP in common forms of B-cell non-Hodgkin’s lymphoma, such as follicular lymphoma and diffuse large B-cell lymphoma [27]. These studies clearly establish p300 and CBP as major players in different types of cancer and are consistent with their roles both as transcriptional co-activators for the major tumour suppressor p53 and many other DNA-binding transcription factors. MYST proteins In addition to the alteration of the CBP gene, another striking discovery made during the characterization of the aforementioned t(8;16) chromosomal translocation was that the translocation partner encodes a protein, called MOZ, containing a 200-residue module that is highly homologous with TIP60 (a partner of HIV Tat) and two yeast proteins (Sas2 and Sas3) involved in gene silencing [19,20]. This module was thus named the MYST domain [19,20]. Consistent with its sequence similarity with an acetyl-CoA-binding motif in GNATs, MOZ was formally shown to possess acetyltransferase activity (reviewed in [10]). It was © The Authors Journal compilation © 2012 Biochemical Society

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later found that the MOZ gene is altered in other recurrent chromosomal translocations in acute myeloblastic or lymphoblastic leukaemia (reviewed in [10]). Human MORF (also referred to as MYST4 and KAT6B) was first identified in 1999 as a protein paralogous to MOZ (reviewed in [10]). Translocations affecting the MORF gene lead to leiomyomata, benign tumours of the uterus. Other translocations fusing MORF to CBP can cause aggressive forms of childhood acute myeloid leukaemia and adult acute myeloid leukaemia (reviewed in [10]). Moreover, haploinsufficiency of the MORF gene was recently identified in a Noonan syndrome-like syndrome patient who displays neural, craniofacial and skeletal defects [28]. This gene is also mutated in multiple Ohdo syndrome individuals with severe intellectual disability and mask-like facial appearance [29], as well as in several genitopatellar syndrome patients who exhibit facial and genital abnormalities along with bone defects, especially the patella (knee cap) [30]. These findings attest to the important role of MORF in multiple tissue or organ systems. TIP60 plays a role in transcriptional regulation and DNA-damage-response pathways [21]. EPC1 is one of the subunits of the TIP60 complex in humans [31], and chromosomal rearrangement with generation of EPC1/PHF1 was found in endometrial stromal sarcoma [32]. hMOF is the human orthologue of Drosophila Mof, a HAT that modifies the X-chromosome chromatin in males to achieve dosage compensation [33]. This acetyltransferase was found to be frequently down-regulated in primary breast carcinoma and medulloblastoma (the most common malignant brain tumour of childhood) and constitutes a potential biomarker for clinical outcome in medulloblastoma [34]. Interestingly, mice specifically deficient of Mof in Purkinje cells (large neurons with many branching extensions) display a similar phenotype to that observed in patients with ataxia telangiectasia, a rare inheritable neurodegenerative disease [35]. HBO1 is overexpressed in primary cancers, including testicular germ cell tumours, breast adenocarcinomas and ovarian serous carcinomas [36]. GNATs Although this group is much larger than the p300/CBP and MYST families, direct links to diseases are relatively few. Two exceptions are ELP3 and ESCO2. The acetyltransferase ELP3 and an associated scaffold protein (ELP1) have been linked to the motor neuron disease amyotrophic lateral sclerosis (also widely known as Lou Gehrig disease after the famous baseball player) [37] and familial dysautonomia (a inheritable nervous system disorder) [38]. Yeast Eco1 and its mammalian orthologues, ESCO1 and ESCO2, play key roles in regulating sister chromatid cohesion [5], and mutations in ESCO2 are associated with Roberts syndrome, an autosomal recessive disorder characterized by slow growth, mental retardation and limb defects [39]. As shown in the recent connection of MORF made to Noonan syndromelike syndrome [28], Ohdo syndrome [29] and genitopatellar syndrome [30], it may take many years from the initial molecular identification of a protein to the © The Authors Journal compilation © 2012 Biochemical Society

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discovery of disease-associated mutations. It is thus likely that future studies will provide new cases to link the GNAT family to human diseases.

HDACs (histone deacetylases) and direct links to human diseases A few months after the report of GCN5 as a KAT [8], the first HDAC was identified [40]. Since then, it has been shown that the human genome encodes 18 KDACs [41]. On the basis of sequence similarity to yeast prototypes, they are divided into two families [42]. While 11 of them belong to the Rpd3/Hda1 (reduced potassium dependency 3/histone deacetylase 1) family, seven are considered as members of the sirtuin [Sir2 (silent information regulator 2)-related protein] family [43]. The two families utilize different catalytic mechanisms (Figure 1). Depending on how similar they are when compared with yeast Rpd3 and Hda1, members of the Rpd3/Hda1 family have been grouped into three classes: I, II and IV [44]. Among class II, there are six members and, according to sequence similarity, they are further divided into two subgroups, IIa (four members) and IIb (two members) [41]. According to this classification scheme, sirtuins are considered to form class III. Numerous studies of these enzymes at the molecular, cellular and organismal levels have clearly established their importance in different cellular and developmental processes. In support of this, deacetylase inhibitors have been actively evaluated as novel therapeutics for cancer, neurodegenerative disorders and various other diseases. Several recent studies have directly linked class IIa HDACs to genetic diseases. First, mutations of the HDAC4 gene are present in patients of brachydactyly mental retardation syndrome with intellectual disabilities, developmental delays, and craniofacial and skeletal abnormalities [45]. Related to this, HDAC4deficient mice display defects in bone and brain development [46]. Secondly, a genome-wide association study with a large human population has recently identified HDAC4 as one of 16 loci influencing lung functions [47]. Thirdly, HDAC4 and other class IIa members serve as transcriptional co-repressors of the MEF2 (myocyte enhancer factor 2) family of DNA-binding transcription factors [48]. The binding of class IIa HDACs to MEF2 results in transcriptional repression, and phosphorylation of the HDACs by protein kinases relieves this repression. In humans, there are four MEF2 proteins, MEF2A, B, C and D [48]. MEF2B somatic mutations have been identified in the two most common types of non-Hodgkin lymphomas, follicular lymphoma and diffuse large B-cell lymphoma [49]. MEF2C was recently identified as the driving oncogene for immature T-cell acute lymphoblastic leukaemia [50]. The MEF2D gene is rearranged in pre-B acute lymphoblastic leukaemia with translocation between chromosomes 1 and 19 [51], and the murine MEF2D gene was identified as an oncogenic candidate in leukaemogenesis [52]. Thus the MEF2–class IIa HDAC regulatory axis is of importance to human health and subject to frequent alteration in human diseases. © The Authors Journal compilation © 2012 Biochemical Society

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It should be noted that HDAC4 was first identified in 1999 (reviewed in [41]), and the disease-linked mutation was just discovered recently [45], reiterating the idea that it may take many years to link a molecular player directly to human disease. This is also likely to be true for other members of the HDAC superfamily.

Bromodomains and their links to human diseases While the acetyltransferases and deacetylases maintain the dynamic levels of lysine acetylation, bromodomain-containing proteins serve as key effectors by forming specific binding pockets for recognizing this modification. The bromodomain was initially identified as a conserved sequence module shared by several chromatin regulators and was subsequently shown to serve as a structural unit recognizing acetyl-lysine-containing peptide motifs [53]. This domain is conserved from yeast to humans, and there are over 40 bromodomain-containing proteins in humans. Some acetyltransferases, such as GCN5, PCAF, p300 and CBP, also contain bromodomains. As discussed above, both p300 and CBP have been directly linked to a genetic disease and leukaemia. In addition, emerging studies have uncovered important links of BRD4 (bromodomain-containing protein 4) to several types of cancer: (i) balanced translocation between chromosomes 15q13 and 19p13 results in fusion of the BRD4 gene to that of NUT (nuclear protein in testis), a rare and lethal form of carcinoma [54]; (ii) a genomewide screen by RNA interference identified BRD4 as a therapeutic target in acute myeloid leukaemia [55]; (iii) BRD4 activation predicts the survival of patients with breast cancer [56]; and (iv) BRD4 is a member of the BET (bromodomain and extraterminal) subfamily of human bromodomain proteins, and BET inhibition down-regulates c-Myc transcription in experimental models of multiple myeloma [57].

Perspective From the initial discovery in the 1960s to the recent elucidation of acetylomes, lysine acetylation has emerged as a major PTM that is important for regulating diverse cellular processes in various organisms from bacteria to humans. Since their initial identification in the 1990s, KATs, KDACs and acetyl-lysinerecognizing bromodomain proteins have been firmly established to play important roles in controlling lysine acetylation and mediating its actions. As emphasized in the present chapter, recent studies have provided direct links of these three groups of proteins to human diseases. This trend is likely to continue in the coming few years. The recent studies also reiterate that fundamental research of these proteins is highly important for uncovering and comprehending related clinical discoveries. One recurrent theme is that it often takes many years to translate results from fundamental research to a clinical setting, thus raising an interesting issue about how to facilitate the translation. One possible © The Authors Journal compilation © 2012 Biochemical Society

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remedy is to stimulate the exchange of information and the interaction between basic researchers and clinical scientists. Summary • •

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Lysine acetylation plays an important role in regulating chromatin function. In addition to chromatin function, lysine acetylation is important for controlling other processes in eukaryotic cells, and even occurs in bacteria. Lysine acetyltransferases and deacetylases govern the dynamic level of lysine acetylation in vivo. Bromodomains are able to recognize acetyl-lysine-containing peptides. KATs, KDACs and GNATs have been linked to various human diseases, including leukaemia, heart disease, neurodegenerative disorders and bone abnormalities. Thus these proteins are important molecular targets for developing novel therapeutics.

The work of the authors is supported by CIHR (Canadian Institutes of Health Research), Canadian Cancer Society, NSERC (Natural Sciences and Engineering Research Council of Canada) and MDEIE (Développement économique, innovation et exportation) Québec (to X.J.Y.). L.Y. received a training award (FRN53888) from the CIHR-McGill Integrated Cancer Research Training Program.

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