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Histone acetyltransferases (HATs) are enzymes that
acetylate In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
conserved
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −CO ...
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s on histone proteins by transferring an
acetyl group In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
from
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression. In general, histone acetylation is linked to
transcriptional Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
activation and associated with euchromatin. Euchromatin, which is less densely compact, allows transcription factors to bind more easily to regulatory sites on DNA, causing transcriptional activation. When it was first discovered, it was thought that
acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposit ...
of lysine neutralizes the positive
charge Charge or charged may refer to: Arts, entertainment, and media Films * ''Charge, Zero Emissions/Maximum Speed'', a 2011 documentary Music * ''Charge'' (David Ford album) * ''Charge'' (Machel Montano album) * '' Charge!!'', an album by The Aqu ...
normally present, thus reducing affinity between histone and (negatively charged) DNA, which renders DNA more accessible to
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
. Research has emerged, since, to show that lysine acetylation and other posttranslational modifications of histones generate binding sites for specific protein–protein interaction domains, such as the acetyllysine-binding
bromodomain A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the ''N''-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducin ...
. Histone acetyltransferases can also acetylate non-histone proteins, such as nuclear receptors and other transcription factors to facilitate gene expression.


HAT families

HATs are traditionally divided into two different classes based on their subcellular localization. Type A HATs are located in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
and are involved in the regulation of gene expression through acetylation of nucleosomal histones in the context of chromatin. They contain a
bromodomain A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the ''N''-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducin ...
, which helps them recognize and bind to acetylated lysine residues on histone substrates. Gcn5, p300/CBP, and TAFII250 are some examples of type A HATs that cooperate with activators to enhance transcription. Type B HATs are located in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
and are responsible for acetylating newly synthesized histones prior to their assembly into nucleosomes. These HATs lack a bromodomain, as their targets are unacetylated. The acetyl groups added by type B HATs to the histones are removed by HDACs once they enter the nucleus and are incorporated into
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in ...
.
Hat1 Histone acetyltransferase 1, also known as HAT1, is an enzyme that, in humans, is encoded by the ''HAT1'' gene. Function The protein encoded by this gene is a type B histone acetyltransferase (HAT) that is involved in the rapid acetylation of n ...
is one of the few known examples of a type B HAT. Despite this historical classification of HATs, some HAT proteins function in multiple complexes or locations and would thus not easily fit into a particular class.


Gcn5-related ''N''-acetyltransferases (GNATs)

HATs can be grouped into several different families based on sequence homology as well as shared structural features and functional roles. The Gcn5-related ''N''-acetyltransferase (GNAT) family includes Gcn5,
PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. Structure Several domains of PCAF can act independently or in unison to enable its funct ...
, Hat1, Elp3, Hpa2, Hpa3, ATF-2, and Nut1. These HATs are generally characterized by the presence of a bromodomain, and they are found to acetylate lysine residues on histones H2B, H3, and H4. All members of the GNAT family are characterized by up to four conserved motifs (A-D) found within the catalytic HAT domain. This includes the most highly conserved motif A, which contains an Arg/Gln-X-X-Gly-X-Gly/Ala sequence that is important for
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
recognition and binding. The C motif is found in most GNATs, but it is not present in the majority of other known HATs. The yeast Gcn5 (general control nonderepressible-5) HAT is one of the best-characterized members of this family. It has four functional domains, including an N-terminal domain, a highly conserved catalytic (HAT) domain, an Ada2 interaction domain, and a C-terminal bromodomain. PCAF (p300/CBP-associated factor) and GCN5 are mammalian GNATs that share a high degree of homology throughout their sequences. These proteins have a 400-residue N-terminal region that is absent in yeast Gcn5, but their HAT functions are evolutionarily conserved with respect to the latter. Hat1 was the first HAT protein to be identified. It is responsible for most of the cytoplasmic HAT activity in yeast, and it binds strongly to histone H4 by virtue of its association with an additional subunit, Hat2. Elp3 is an example of a type A HAT found in yeast. It is part of the
RNA polymerase II holoenzyme RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins ...
and plays a role in transcriptional elongation.


MYST HATs

The MYST family of HATs is named after its four founding members MOZ, Ybf2 (Sas3), Sas2, and Tip60. Other important members include Esa1, MOF, MORF, and HBO1. These HATs are typically characterized by the presence of zinc fingers and
chromodomain A chromodomain (''chromatin organization modifier'') is a protein structural domain of about 40–50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. The domain is highly conserved amon ...
s, and they are found to acetylate lysine residues on histones H2A, H3, and H4. Several MYST family proteins contain zinc fingers as well as the highly conserved motif A found among GNATs that facilitates acetyl-CoA binding. A cysteine-rich region located in the N terminus of the HAT domain of MYST proteins is involved in zinc binding, which is essential for HAT activity. Tip60 (Tat-interactive protein, 60 kDa) was the first human MYST family member to exhibit HAT activity. Sas3 found in yeast is a homolog of MOZ (monocytic leukemia zinc finger protein), which is an oncogene found in humans. Esa1 was the first essential HAT to be found in yeast, and MOF is its homolog in fruit flies. The HAT activity of the latter is required for the twofold increased transcription of the male X chromosome (
dosage compensation Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes are often characterized by different types and numbers of sex chromosomes. In order ...
) in flies. Human HBO1 (HAT bound to ORC1) was the first HAT shown to associate with components of the origin of replication complex. MORF (MOZ-related factor) exhibits very close homology to MOZ throughout its entire length. It contains an N-terminal repression region that decreases its HAT activity ''in vitro'' as well as a C-terminal activation domain that is functional in the absence of the HAT domain.


Others

In addition to those that are members of the GNAT and MYST families, there are several other proteins found typically in higher eukaryotes that exhibit HAT activity. These include p300/CBP, nuclear receptor coactivators (e.g., ACTR/SRC-1), TAFII250, TFIIIC, Rtt109, and
CLOCK A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and the ...
. p300/CBP are metazoan-specific and contain several zinc finger regions, a bromodomain, a catalytic (HAT) domain, and regions that interact with other transcription factors. Importantly, the HAT domain shows no sequence homology to other known HATs, and it is required for p300/CBP to function in transcriptional activation. In addition, these proteins contain several HAT domain motifs (A, B, and D) that are similar to those of the GNATs. They also possess a novel motif E that is homologous to sequences in the HAT domains of GNATs. TFIIIC is one of the general transcription factors involved in RNA polymerase III-mediated transcription. Three components in the human protein have been shown to possess independent HAT activity ( hTFIIIC220, hTFIIIC110, and hTFIIIC90). Rtt109 is a fungal-specific HAT that requires association with histone chaperone proteins for activity. The HAT activities of the human TAFII250 and CLOCK coactivators have not been studied as extensively. TAFII250 is one of the TBP-associated factor subunits of
TFIID Transcription factor II D (TFIID) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters ...
, and it shares a Gly-X-Gly pattern with Gcn5 that is important for HAT activity. CLOCK is a circadian rhythm master regulator that functions with
BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
to carry out its HAT activity.


Nuclear receptor coactivators

Three important nuclear receptor coactivators that display HAT activity are
SRC-1 The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by l ...
, ACTR, and TIF-2. Human SRC-1 (steroid receptor coactivator-1) is known to interact with p300/CBP and PCAF, and its HAT domain is located in its C-terminal region. ACTR (also known as RAC3, AIB1, and TRAM-1 in humans) shares significant sequence homology with SRC-1, in particular in the N-terminal and C-terminal (HAT) regions as well as in the receptor and coactivator interaction domains. ACTR also interacts with p300/CBP and PCAF. The former can prevent ACTR from binding to and activating its receptor by acetylating it in its receptor interaction domain. TIF-2 (transcriptional intermediary factor 2; also known as GRIP1) is another nuclear receptor coactivator with HAT activity, and it also interacts with p300/CBP. A table summarizing the different families of HATs along with their associated members, parent organisms, multisubunit complexes, histone substrates, and structural features is presented below.


Overall structure

In general, HATs are characterized by a structurally conserved core region made up of a three-stranded
β-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...
followed by a long
α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...
parallel to and spanning one side of it. The core region, which corresponds to motifs A, B, and D of the GNAT proteins, is flanked on opposite sides by N- and C-terminal α/β segments that are structurally unique for a given HAT family. The central core and the flanking segments together form a cleft over the former, which is where histone substrates can bind prior to catalysis. While the central core domain (motif A in GNATs) is involved in acetyl-CoA binding and catalysis, the N- and C-terminal segments assist in binding histone substrates. Unique features related to the sequence and/or structure of the N- and C-terminal regions for different HAT families may help to explain some observed differences among HATs in histone substrate specificity. CoA binding has been observed to widen the histone binding groove in the central core by moving the C-terminal segment of Gcn5 outward. In addition, since contacts between CoA and protein facilitate the formation of favorable histone-protein contacts, it is likely that CoA binding precedes histone binding ''in vivo''.


GNAT and MYST families

HATs in the GNAT family are most notably characterized by an approximately 160-residue HAT domain and a C-terminal bromodomain, which binds to acetylated lysine residues. Those in the MYST family have HAT domains that are about 250 residues in length. Many MYST proteins also contain a cysteine-rich, zinc-binding domain within the HAT region in addition to an N-terminal chromodomain, which binds to methylated lysine residues. On a broader scale, the structures of the catalytic domains of GNAT proteins (Gcn5, PCAF) exhibit a mixed α/β globular fold with a total of five α-helices and six β-strands. The overall topology resembles a
vise A vise or vice (British English) is a mechanical apparatus used to secure an object to allow work to be performed on it. Vises have two parallel jaws, one fixed and the other movable, threaded in and out by a screw and lever. A vise grip is n ...
, with the central core of the protein at the base and the N- and C-terminal segments on the sides.


p300/CBP family

The p300/CBP HATs have larger HAT domains (about 500 residues) than those present in the GNAT and MYST families. They also contain a bromodomain as well as three cysteine/histidine-rich domains that are thought to mediate interactions with other proteins. The structure of p300/CBP is characterized by an elongated globular domain, which contains a seven-stranded β-sheet in the center that is surrounded by nine α-helices and several loops. The structure of the central core region associated with acetyl-CoA binding is conserved with respect to GNAT and MYST HATs, but there are many structural differences in the regions flanking this central core. Overall, the structural data is consistent with the fact that p300/CBP HATs are more promiscuous than GNAT and MYST HATs with respect to substrate binding.


Rtt109

The structure of Rtt109 is very similar to that of p300, despite there only being 7% sequence identity between the two proteins. There is a seven-stranded β-sheet that is surrounded by α-helices as well as a loop that is involved in acetyl-CoA substrate binding. Despite the conserved structure, Rtt109 and p300/CBP are functionally unique. For instance, the substrate binding site of the former is more similar to that of the GNAT and MYST HATs. In addition, the residues in the active site of each enzyme are distinct, which suggests that they employ different catalytic mechanisms for acetyl group transfer.


Catalytic mechanisms

The basic mechanism catalyzed by HATs involves the transfer of an acetyl group from acetyl-CoA to the ε-amino group of a target lysine side-chain within a histone. Different families of HATs employ unique strategies in order to effect such a transformation.


GNAT family

Members of the GNAT family have a conserved glutamate residue that acts as a general base for catalyzing the nucleophilic attack of the lysine amine on the acetyl-CoA thioester bond. These HATs use an ordered sequential bi-bi mechanism wherein both substrates (acetyl-CoA and histone) must bind to form a
ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, for exampl ...
with the enzyme before catalysis can occur. Acetyl-CoA binds first, followed by the histone substrate. A conserved glutamate residue (Glu173 in yeast Gcn5) activates a water molecule for removal of a proton from the amine group on lysine, which activates it for direct nucleophilic attack on the carbonyl carbon of enzyme-bound acetyl-CoA. After the reaction, the acetylated histone is released first followed by CoA.


MYST family

Studies of yeast Esa1 from the MYST family of HATs have revealed a
ping-pong mechanism Enzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in th ...
involving conserved glutamate and cysteine residues. The first part of the reaction involves the formation of a covalent intermediate in which a cysteine residue becomes acetylated following nucleophilic attack of this residue on the carbonyl carbon of acetyl-CoA. Then, a glutamate residue acts as a general base to facilitate transfer of the acetyl group from the cysteine to the histone substrate in a manner analogous to the mechanism used by GNATs. When Esa1 is assembled in the piccolo NuA4 complex, it loses its dependence on the cysteine residue for catalysis, which suggests that the reaction may proceed via a ternary bi-bi mechanism when the enzyme is part of a physiologically relevant multiprotein complex.


p300/CBP family

In human p300, Tyr1467 acts as a general acid and Trp1436 helps orient the target lysine residue of the histone substrate into the active site. These two residues are highly conserved within the p300/CBP HAT family and, unlike enzymes in the GNAT and MYST families, p300 does not employ a general base for catalysis. Rather, it is likely that members of the p300/CBP family use a Theorell-Chance (i.e., “hit-and-run”) acetyl transfer mechanism.


Rtt109

Rtt109 is likely to employ a mechanism that is different from that of the other HATs. The yeast enzyme has very low catalytic activity in the absence of the histone chaperone proteins Asf1 and Vps75, which may be involved in delivering histone substrates to the enzyme for acetylation. Moreover, a general acid or base have not yet been identified for this HAT.


Substrate binding and specificity

The structures of several HAT domains bound to acetyl-CoA and histone substrate peptides reveal that the latter bind across a groove on the protein that is formed by the central core region at the base and is flanked on opposite sides by the variable N- and C-terminal segments that mediate the majority of the interactions with the substrate peptide. It is likely that these variable regions are at least in part responsible for the observed specificity of different HATs for various histone substrates. Members of the GNAT and MYST families as well as Rtt109 exhibit greater substrate selectivity than p300/CBP, which is rather promiscuous with regard to substrate binding. Whereas it appears that only three to five residues on either side of the lysine to be acetylated are necessary for effective substrate binding and catalysis by members of the GNAT and p300/CBP families, more distal regions of the substrate may be important for efficient acetylation by MYST family HATs.


Lysine selectivity

Different HATs, usually in the context of multisubunit complexes, have been shown to acetylate specific lysine residues in histones.


GNAT family

Gcn5 cannot acetylate nucleosomal histones in the absence of other protein factors. In the context of complexes like SAGA and ADA, however, Gcn5 is able to acetylate H3K14 among other sites within histones H2B, H3, and H4 (e.g., H3K9, H3K36, H4K8, H4K16). Both Gcn5 and PCAF have the strongest site preference for H3K14, either as a free histone or within a nucleosome. Hat1 acetylates H4K5 and H4K12, and Hpa2 acetylates H3K14 ''in vitro''.


MYST family

In flies, acetylation of H4K16 on the male X chromosome by MOF in the context of the MSL complex is correlated with transcriptional upregulation as a mechanism for dosage compensation in these organisms. In humans, the MSL complex carries out the majority of genome-wide H4K16 acetylation. In the context of their cognate complexes, Sas2 (SAS) and Esa1 (NuA4) also carry out acetylation of H4K16, in particular in the telomere regions of chromosomes. Sas2 is also observed to acetylate H3K14 ''in vitro'' on free histones. Esa1 can also acetylate H3K14 ''in vitro'' on free histones as well as H2AK5, H4K5, H4K8, and H4K12 either ''in vitro'' or ''in vivo'' on nucleosomal histones. H2AK7 and H2BK16 are also observed to be acetylated by Esa1 ''in vivo''. Notably, neither Sas2 nor Esa1 can acetylate nucleosomal histones ''in vitro'' as a free enzyme. This happens to be the case as well for Sas3, which is observed to acetylate H3K9 and H3K14 ''in vivo'' as well as lysine residues on H2A and H4. MOZ can also acetylate H3K14.


Others

p300/CBP acetylate all four nucleosomal core histones equally well. ''In vitro'', they have been observed to acetylate H2AK5, H2BK12, H2BK15, H3K14, H3K18, H4K5, and H4K8. SRC-1 acetylates H3K9 and H3K14, TAFII230 (Drosophila homolog of human TAFII250) acetylates H3K14, and Rtt109 acetylates H3K9, H3K23, and H3K56 in the presence of either Asf1 or Vps75.


Non-histone substrates (''in vitro'')

In addition to the core histones, certain HATs acetylate a number of other cellular proteins including transcriptional activators, basal transcription factors, structural proteins,
polyamine A polyamine is an organic compound having more than two amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. ...
s, and proteins involved in nuclear import. Acetylation of these proteins can alter their ability to interact with their cognate DNA and/or protein substrates. The idea that acetylation can affect protein function in this manner has led to inquiry regarding the role of acetyltransferases in signal transduction pathways and whether an appropriate analogy to
kinases In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...
and phosphorylation events can be made in this respect.


PCAF

PCAF and p300/CBP are the main HATs that have been observed to acetylate a number of non-histone proteins. For PCAF, these include the non-histone chromatin ( high-mobility group (HMG)) proteins HMG-N2/HMG17 and HMG-I(Y), the transcriptional activators
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
, MyoD, E2F(1-3), and HIV Tat, and the general transcription factors
TFIIE Transcription factor II E (TFIIE) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is a tetramer of two alpha and two beta chains and interacts with TAF6/TAFII80, ATF7IP, and varicella ...
and
TFIIF Transcription factor II F (TFIIF) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. TFIIF is encoded by the , , and genes. TFIIF binds to RNA polymerase II RNA polymerase II (RNAP II ...
. Other proteins include
CIITA CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator. Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and ...
, Brm (chromatin remodeler), NF-κB (p65), TAL1/SCL, Beta2/NeuroD, C/EBPβ,
IRF2 Interferon regulatory factor 2 is a protein that in humans is encoded by the ''IRF2'' gene. Function IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhi ...
,
IRF7 Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors. Function IRF7 encodes interferon regulatory factor 7, a member of the interferon regulatory transcription fac ...
,
YY1 YY1 (Yin Yang 1) is a transcriptional repressor protein in humans that is encoded by the YY1 gene. Function YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins. The protein is inv ...
, KLF13, EVI1, AME, ER81, and the androgen receptor (AR). PCAF has also been observed to acetylate
c-MYC ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
, GATA-2, retinoblastoma (Rb),
Ku70 Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene. Function Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway ...
, and E1A adenovirus protein. It can also autoacetylate, which facilitates intramolecular interactions with its bromodomain that may be involved in the regulation of its HAT activity.


p300/CBP

p300/CBP have many non-histone substrates, including the non-histone chromatin proteins HMG1, HMG-N1/HMG14, and HMG-I(Y), the transcriptional activators p53, c-Myb, GATA-1,
EKLF Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturati ...
, TCF, and HIV Tat, the nuclear receptor coactivators ACTR, SRC-1, and TIF-2, and the general transcription factors TFIIE and TFIIF. Other substrates include the transcription factors Sp1,
KLF5 Krueppel-like factor 5 is a protein that in humans is encoded by the ''KLF5'' gene. Function This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. Since the protein localizes to the nucleus and binds the epi ...
,
FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
,
MEF2C Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the ''MEF2C'' gene. MEF2C is a transcription factor in the Mef2 family. Genomics The gene is l ...
, SRY, GATA-4, and HNF-6, HMG-B2,
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
, the androgen and estrogen (α) receptors, GATA-2, GATA-3, MyoD, E2F(1-3),
p73 p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized ...
α, retinoblastoma (Rb), NF-κB (p50, p65),
Smad7 Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the ''SMAD7'' gene. SMAD7 is a protein that, as its name describes, is a homolog of the Drosophila gene: "Mothers against decapentaplegic". It belongs t ...
, importin-α, Ku70,
YAP1 YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcription coregulator that promotes transcription of genes involved in cellular proliferation and suppressing apoptotic genes. YAP1 is a component in t ...
, E1A adenovirus protein, and S-HDAg (
hepatitis delta virus Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV). HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite (a type of subviral agent) because it can propagate only in ...
small delta antigen). p300/CBP have also been observed to acetylate
β-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
, RIP140, PCNA, the DNA metabolic enzymes flap endonuclease-1, thymine DNA glycosylase, and Werner syndrome DNA helicase,
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor c ...
, Runx1 (AML1), UBF, Beta2/NeuroD,
CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
,
c-Jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only l ...
, C/EBPβ, NF-E2,
SREBP Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes '' SREBF1'' and '' SREBF2''. SREBPs belong to the basic ...
, IRF2, Sp3, YY1, KLF13, EVI1,
BCL6 Bcl-6 (B-cell lymphoma 6) is a protein that in humans is encoded by the ''BCL6'' gene. BCL6 is a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation. BCL6 has three evolutionary conserved structural d ...
, HNF-4, ER81 and FOXO4 (AFX).


Multisubunit HAT complexes

The formation of multisubunit complexes has been observed to modulate the substrate specificity of HATs. In general, while recombinant HATs are able to acetylate free histones, HATs can acetylate nucleosomal histones only when they are in their respective ''in vivo'' HAT complexes. Some of the proteins that associate with HATs in these complexes function by targeting the HAT complex to nucleosomes at specific regions in the genome. For instance, it has been observed that HAT complexes (e.g. SAGA, NuA3) often use methylated histones as docking sites so that the catalytic HAT subunit can carry out histone acetylation more effectively. In addition, the formation of multisubunit HAT complexes influences the lysine specificity of HATs. The specific lysine residues that a given HAT acetylates may become either broader or more restricted in scope upon association with its respective complex. For example, the lysine specificity of MYST family HATs toward their histone substrates becomes more restricted when they associate with their complexes. In contrast, Gcn5 acquires the ability to acetylate multiple sites in both histones H2B and H3 when it joins other subunits to form the SAGA and ADA complexes. Moreover, the acetylation site specificity of Rtt109 is dictated by its association with either Vps75 or Asf1. When in complex with the former, Rtt109 acetylates H3K9 and H3K27, but, when in complex with the latter, it preferentially acetylates H3K56.


Regulation of HAT activity

The catalytic activity of HATs is regulated by two types of mechanisms: (1) interaction with regulatory protein subunits and (2) autoacetylation. A given HAT may be regulated in multiple ways, and the same effector may actually lead to different outcomes under different conditions. Although it is clear that the association of HATs with multiprotein complexes provides a mechanism for the regulation of both HAT activity and substrate specificity ''in vivo'', the molecular basis for how this actually occurs is still largely unknown. However, data suggests that associated subunits may contribute to catalysis at least in part by facilitating productive binding of the HAT complex to its native histone substrates. The MYST family of HATs, p300/CBP, and Rtt109 have all been shown to be regulated by autoacetylation. Human MOF as well as yeast Esa1 and Sas2 are autoacetylated at a conserved active site lysine residue, and this modification is required for their function ''in vivo''. Human p300 contains a highly basic loop embedded in the middle of its HAT domain that is hyperacetylated in the active form of the enzyme. It has been proposed that, upon autoacetylation, this loop is released from the electronegative substrate binding site where it sits in the inactive HAT. Acetylation of yeast Rtt109 at Lys290 is also required for it to exhibit full catalytic activity. Some HATs are also inhibited by acetylation. For example, the HAT activity of the nuclear receptor coactivator ACTR is inhibited upon acetylation by p300/CBP.


Interaction with HDACs

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are recruited to their target promoters through physical interactions with sequence-specific transcription factors. They usually function within a multisubunit complex in which the other subunits are necessary for them to modify histone residues around the binding site. These enzymes can also modify non-histone proteins.


Biological role


Chromatin remodeling

Histone acetyltransferases serve many biological roles inside the cell.
Chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in ...
is a combination of proteins and DNA found in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
, and it undergoes many structural changes as different cellular events such as DNA replication, DNA repair, and transcription occur. Chromatin in the cell can be found in two states: condensed and uncondensed. The latter, known as euchromatin, is transcriptionally active, whereas the former, known as
heterochromatin Heterochromatin is a tightly packed form of DNA or '' condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role ...
, is transcriptionally inactive. Histones comprise the protein portion of chromatin. There are five different histone proteins: H1, H2A, H2B, H3, and H4. A core histone is formed when two of each histone subtype, excluding H1, form a quaternary complex. This octameric complex, in association with the 147 base pairs of DNA coiled around it, forms the nucleosome. Histone H1 locks the nucleosome complex together, and it is the last protein to bind in the complex. Histones tend to be positively charged proteins with N-terminal tails that stem from the core. The phosphodiester backbone of DNA is negative, which allows for strong ionic interactions between histone proteins and DNA. Histone acetyltransferases transfer an
acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
group to specific
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −CO ...
residues on histones, which neutralizes their positive charge and thus reduces the strong interactions between the histone and DNA. Acetylation is also thought to perturb interactions between individual nucleosomes and act as interaction sites for other DNA-associated proteins. There can be different levels of histone acetylation as well as other types of modifications, allowing the cell to have control over the level of chromatin packing during different cellular events such as replication, transcription, recombination, and repair. Acetylation is not the only regulatory
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosom ...
to histones that dictates chromatin structure; methylation, phosphorylation, ADP-ribosylation, and ubiquitination have also been reported. These combinations of different covalent modifications on the N-terminal tails of histones have been referred to as the
histone code The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications (known as ''histone marks'') to histone proteins, primarily on their unstructured ends. Together with sim ...
, and it is thought that this code may be heritable and preserved in the next cell generation. H3 and H4 histone proteins are the primary targets of HATs, but H2A and H2B are also acetylated ''in vivo''. Lysines 9, 14, 18, and 23 of H3 and lysines 5, 8, 12, and 16 of H4 are all targeted for acetylation. Lysines 5, 12, 15, and 20 are acetylated on histone H2B, while only lysines 5 and 9 have been observed to be acetylated on histone H2A. With so many different sites for acetylation, a high level of specificity can be achieved in triggering specific responses. An example of this specificity is when histone H4 is acetylated at lysines 5 and 12. This acetylation pattern has been seen during histone synthesis. Another example is acetylation of H4K16, which has been associated with dosage compensation of the male X chromosome in ''Drosophila melanogaster''.


Gene expression

Histone modifications modulate the packing of chromatin. The level of packing of the DNA is important for gene transcription, since the transcriptional machinery must have access to the promoter in order for transcription to occur. Neutralization of charged lysine residues by HATs allows for the chromatin to decondense so that this machinery has access to the gene to be transcribed. However, acetylation is not always associated with enhanced transcriptional activity. For instance, acetylation of H4K12 has been associated with condensed and transcriptionally inactive chromatin. In addition, some histone modifications are associated with both enhanced and repressed activity, in a context-dependent manner. HATs act as transcriptional co-activators or gene silencers and are most often found in large complexes made up of 10 to 20 subunits, some of which shared among different HAT complexes. These complexes include SAGA (Spt/Ada/Gcn5L acetyltransferase), PCAF, ADA (transcriptional adaptor), TFIID (transcription factor II D), TFTC (TBP-free TAF-containing complex), and NuA3/NuA4 (nucleosomal acetyltransferases of H3 and H4). These complexes modulate HAT specificity by bringing HATs to their target genes where they can then acetylate nucleosomal histones. Some HAT transcriptional co-activators contain a
bromodomain A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the ''N''-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducin ...
, a 110-amino acid module that recognizes acetylated lysine residues and is functionally linked to the co-activators in the regulation of transcription.


Clinical significance

The ability of histone acetyltransferases to manipulate chromatin structure and lay an
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
framework makes them essential in cell maintenance and survival. The process of chromatin remodeling involves several enzymes, including HATs, that assist in the reformation of nucleosomes and are required for DNA damage repair systems to function. HATs have been implicated as accessories to disease progression, specifically in neurodegenerative disorders. For instance, Huntington's disease is a disease that affects motor skills and mental abilities. The only known mutation that has been implicated in the disease is in the N-terminal region of the protein huntingtin (htt). It has been reported that htt directly interacts with HATs and represses the catalytic activity of p300/CBP and PCAF ''in vitro''. The human premature aging syndrome Hutchinson Gilford
progeria Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...
is caused by a mutational defect in the processing of
lamin A Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, r ...
, a nuclear matrix protein. In a mouse model of this condition, recruitment of
repair The technical meaning of maintenance involves functional checks, servicing, repairing or replacing of necessary devices, equipment, machinery, building infrastructure, and supporting utilities in industrial, business, and residential installa ...
proteins to sites of DNA damage is delayed. The molecular mechanism underlying this delayed repair response involves a histone acetylation defect. Specifically, histone H4 is hypoacetylated at a lysine 16 residue (H4K16) and this defect is due to reduced association of histone acetyltransferase, Mof, to the nuclear matrix
Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cere ...
is a neurodegenerative disease that arises as a result of a defective mutant Ataxin-1 protein. Mutant Ataxin-1 reduces histone acetylation resulting in repressed histone acetyltransferase-mediated transcription. HATs have also been associated with control of learning and memory functions. Studies have shown that mice without PCAF or CBP display evidence of
neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
. Mice with PCAF deletion are incompetent with respect to learning, and those with CBP deletion seem to suffer from long-term memory loss. The misregulation of the equilibrium between acetylation and deacetylation has also been associated with the manifestation of certain cancers. If histone acetyltransferases are inhibited, then damaged DNA may not be repaired, eventually leading to cell death. Controlling the
chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
process within cancer cells may provide a novel drug target for cancer research. Attacking these enzymes within cancer cells could lead to increased
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
due to high accumulation of DNA damage. One such inhibitor of histone acetyltransferases is called garcinol. This compound is found within the rinds of the
garcinia indica ''Garcinia indica'', a plant in the mangosteen family (Clusiaceae), commonly known as ''kokum'', is a fruit-bearing tree that has culinary, pharmaceutical, and industrial uses. It primarily grows in the Western Ghats, especially the Goa and Konka ...
fruit, otherwise known as
mangosteen Mangosteen (''Garcinia mangostana''), also known as the purple mangosteen, is a tropical evergreen tree with edible fruit native to tropical lands surrounding the Indian Ocean. Its origin is uncertain due to widespread prehistoric cultivation. ...
. To explore the effects of garcinol on histone acetyltransferases, researchers used HeLa cells. The cells underwent irradiation, creating double-strand breaks within the DNA, and garcinol was introduced into the cells to see if it influenced the DNA damage response. If garcinol is successful at inhibiting the process of
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
, a DNA repair mechanism that shows preference in fixing double-strand breaks, then it may serve as a
radiosensitizer A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer. Mechanism of action Conventional chemotherapeutics are currently being used in co ...
, a molecule that increases the sensitivity of cells to radiation damage. Increases in radiosensitivity may increase the effectiveness of radiotherapy.


See also

*
Histone-modifying enzymes Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four co ...
* Histone deacetylase (HDAC) * Histone methyltransferase (HMT) *
RNA polymerase control by chromatin structure RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic ...
*
Acetyltransferase Acetyltransferase (or transacetylase) is a type of transferase enzyme that transfers an acetyl group. Examples include: * Histone acetyltransferases including CBP histone acetyltransferase * Choline acetyltransferase * Chloramphenicol acetyltrans ...


References


External links

* {{DEFAULTSORT:Histone Acetyltransferase Transferases EC 2.3.1 Epigenetics