Histone acetyltransferase (HAT) enzymes are a diverse group of proteins that are evolutionarily conserved from yeast to humans.
Although originally identified as enzymes that acetylate histones, a growing number of non-histone substrates have been identified for HATs, which implies a more general role in regulating the function of an ever-growing number of proteins.
Based on structural evidence, HAT enzymes can accommodate a number of substrates; therefore, the functions of these enzymes are much more varied than simply modifying histones post-translationally.
Although the HAT enzyme is the catalytic subunit that is required for activity, it is the context in which these enzymes exist that provides the enzyme with specificity. Most HAT enzymes exist in multiprotein complexes, and it is these proteins that allow the enzymes to carry out specific functions in the cell.
Many HAT-associated proteins contain domains, which can recognize and bind modified protein residues. This includes bromo-, chromo- and PHD (plant homeodomain) domains, which are able to bind modified histones.
HAT enzymes carry out several functions in the cell, ranging from repairing regions of DNA damage to maintaining overall genomic integrity.
Future work needs to focus on understanding developmental and tissue-specific HAT complexes while continuing to explore the mechanisms by which an organism maintains the balance of acetylation.
Over the past 10 years, the study of histone acetyltransferases (HATs) has advanced significantly, and a number of HATs have been isolated from various organisms. It emerged that HATs are highly diverse and generally contain multiple subunits. The functions of the catalytic subunit depend largely on the context of the other subunits in the complex. We are just beginning to understand the specialized roles of HAT complexes in chromosome decondensation, DNA-damage repair and the modification of non-histone substrates, as well as their role in the broader epigenetic landscape, including the role of protein domains within HAT complexes and the dynamic interplay between HAT complexes and existing histone modifications.
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We are grateful to L. Krom, K. Smith, V. Weake, B. Li, P. Prochasson and M. Carey for helpful discussions and critical reading of the manuscript. We thank W.-J. Shia for the concept in Figure 1 and B. Li and B. Geisbrecht for assistance with Figure 2. We apologize to our colleagues for not being able to quote all references owing to space limitations. K.K.L. was supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation. Research in the Workman laboratory is supported by the US National Institutes of Health.
The authors declare no competing financial interests.
An evolutionarily conserved domain that has been shown to bind to acetylated residues.
A conserved structural motif that is common to some chromosomal proteins. It interacts with chromatin by binding to methylated lysine residues in histone proteins.
- WD40 repeat
A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with tryptophan and aspartic acid (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each blade is a four-stranded β-sheet. This domain is found in proteins of various functions.
- Tudor domain
A domain first identified in the Drosophila melanogaster Tudor protein. Originally identified as an RNA-binding motif, it has also been shown to bind methyl arginine residues and methylated histones.
- PHD finger
(Plant homeodomain). A ∼50-amino-acid motif found mainly in proteins that function in eukaryotic transcription. The characteristic sequence feature is a conserved Cys4-His-Cys3 zinc-binding motif.
- bHLH–PAS domain
A structural motif that is characterized by two helices connected by a loop. Transcription factors that contain this domain are typically dimeric, each with one helix that contains basic amino-acid residues that facilitate DNA binding. Basic helix–loop–helix (bHLH) proteins typically bind to a consensus sequence, CANNTG, which is known as an E-box. The PAS (PER–ARNT–SIM) domain mediates interactions between transcription factors, and most PAS-domain-containing proteins also contain a bHLH domain.
A DNA location with the consensus sequence CANNTG. E-boxes have a regulatory role in the control of transcription. They bind to basic helix–loop–helix (bHLH)-type transcription factors. Binding specificity is determined by the specific bHLH heterodimer or homodimer combination and by the specific nucleotides at the third and fourth position of the E-box sequence.
- Nucleotide excision repair
A DNA-repair process, in which a small region of the DNA strand that surrounds the UV-induced DNA damage is recognized, removed and replaced.
- Double-strand break (DSB) repair
A group of DNA-repair processes that includes homologous recombination and non-homologous end-joining; both processes recognize and repair the DNA double-strand break.
- NAD-dependent histone deacetylase
An enzyme that catalyses the NAD-dependent removal of an acetyl group from lysine residues in histones.
A highly condensed and transcriptionally less active form of chromatin that occurs at defined sites such as centromeres, silencer DNA elements or telomeres.
- Dosage compensation
A process by which the expression of sex-linked genes is equalized in species in which males and females differ in the number of sex chromosomes. In Drosophila melanogaster dosage compensation is achieved by hypertranscription of the single male X chromosome.
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Lee, K., Workman, J. Histone acetyltransferase complexes: one size doesn't fit all. Nat Rev Mol Cell Biol 8, 284–295 (2007). https://doi.org/10.1038/nrm2145
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