The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases

Abstract

Acetylation of the epsilon-amino group of lysine residues, or N(epsilon)-lysine acetylation, is an important post-translational modification known to occur in histones, transcription factors and other proteins. Since 1995, dozens of proteins have been discovered to possess intrinsic lysine acetyltransferase activity. Although most of these enzymes were first identified as histone acetyltransferases and then tested for activities towards other proteins, acetyltransferases only modifying non-histone proteins have also been identified. Lysine acetyltransferases form different groups, three of which are Gcn5/PCAF, p300/CBP and MYST proteins. While members of the former two groups mainly function as transcriptional co-activators, emerging evidence suggests that MYST proteins, such as Esa1, Sas2, MOF, TIP60, MOZ and MORF, have diverse roles in various nuclear processes. Aberrant lysine acetylation has been implicated in oncogenesis. The genes for p300, CBP, MOZ and MORF are rearranged in recurrent leukemia-associated chromosomal abnormalities. Consistent with their roles in leukemogenesis, these acetyltransferases interact with Runx1 (or AML1), one of the most frequent targets of chromosomal translocations in leukemia. Therefore, the diverse superfamily of lysine acetyltransferases executes an acetylation program that is important for different cellular processes and perturbation of such a program may cause the development of cancer and other diseases.

Figure 1

Schematic illustration of the Gcn5/PCAF (A) and p300/CBP (B) families of HATs. Br, bromodomain; Nr, nuclear receptor-interacting box; CH, cysteine/histidine-rich module; KIX, phospho-CREB interacting module; Q, glutamine-rich domain. Numbers on the right correspond to total residues that each protein possesses. In A.thaliana there are five p300/CBP acetyltransferase-related proteins (PCAT1–5), one of which (PCAT2) is depicted here.

Figure 2

Domain organization of MYST proteins from S.cerevisiae (A), Drosophila (B), human (C) and A.thaliana (D). Chromo, chromodomain; Ser, serine-rich domain; CH, cysteine/histidine-rich motif; H15, linker histones H1- and H5-like domain; NEMM, N-terminal part of Enok, MOZ or MORF; PHD, PHD zinc finger; ED, glutamate/aspartate-rich region; SM, serine/methionine-rich domain. The SM domain of MOZ has an insertion of a proline/glutamine-stretch (labeled P). Bars below the N-terminal and SM domains of MORF denote its transcriptional repression and activation domains, respectively. Numbers on the right correspond to the total residues that each protein has.

Figure 3

Diagrams showing how LATs may recognize their substrates. (A) In the ‘hit-and-run’ model, the enzyme–substrate interaction is transient and the substrate dissociates from the enzyme once the reaction is complete. The substrate specificity of the enzyme is mainly determined by its association with the modification site on the substrate. The modification site may reside within a consensus sequence. E, enzyme; S, substrate; Ac, acetylation. (B and C) In the ‘attract-and-hit’ models, the enzyme brings the substrate to the physical proximity either through association with a docking site on the substrate (B) or through the help of an adaptor protein (C). After the reaction, the enzyme may remain associated with the substrate. (D) In the ‘targeted action’ model, the enzyme is recruited to a polymer substrate through an adaptor protein. The adaptor recognizes a specific monomer of the polymer and thus determines the substrate specificity. (E) The ‘relay’ model applies to LATs that possess acetyllysine-binding domains. One acetyltransferase molecule (E1) acetylates one monomer of a polymer substrate and the acetylated monomer then recruits (Re) a second acetyltransferase molecule (E2) via its acetyllysine-binding domain. Acetylation by E2 in turn recruits E1 and leads to the expansion of an acetylation zone. If E1 is the same as E2, the acetylation process is self-perpetuating. (F) Production of HIV TAR RNA at the promoter leads to the recruitment of Tat. Upon acetylation at Lys50 by p300, Tat interacts with the bromodomain of PCAF, which is then targeted to acetylate nearby nucleosomes.

Figure 4

The ε-amino group of a lysine (K) residue is subject to multiple covalent modifications, including ubiquitination, sumoylation, methylation and acetylation (Ac). Acetylation neutralizes the positive charge of the lysine side chain, affects its ability to form hydrogen bonds and creates a new binding surface for protein modules such as the bromodomain.

Figure 5

Schematic illustration of chromosomal abnormalities associated with p300/CBP (A), MOZ/MORF (B) and MLL (C). The breakpoints are indicated with arrows and numbers at their ends represent the amino acid positions. For MLL, the Tapase 1 cleavage sites are also indicated. AT, AT-hook DNA-binding domain; CxxC, zinc finger; SET, histone methyltransferase domain. Other structural domains are labeled as in Figures 1 and 2.

Figure 6

Models explaining how aberrant HATs may lead to leukemogenesis. (A) In normal hematopoietic cells (left), Polycomb group (PcG) proteins repress the expression of HOX genes such as Hox7a and Hox9a, whereas the histone methyltransferase MLL relieves the repression to maintain suitable expression levels when and where it is necessary. The t(11;16)(q23;p13) translocations (Fig. 5) produce MLL-CBP fusion proteins. Unlike wild-type MLL, these fusion proteins cause aberrant acetylation at the HOX loci, which in turn up-regulates the expression of HOX genes and causes the subsequent development of leukemia (middle). A similar mechanism may apply to MLL-p300 fusion proteins derived from the t(11;22)(q23;q13) translocations (Fig. 5). Therefore, inhibitors of p300 and CBP may be of therapeutic value for the treatment of related leukemia (right). (B) In normal hematopoietic cells (left), MOZ functions as a transcriptional co-activator to potentiate Runx1-dependent gene expression and stimulate cell differentiation. The t(8;16)(p11;p13) translocations (Fig. 5) lead to the production of MOZ-CBP fusion proteins. Unlike wild-type MOZ, these fusion proteins down-modulate Runx1-dependent gene expression and thus lead to leukemogenesis (middle). A similar mechanism may operate with other chromosomal abnormalities with aberrant MOZ and MORF genes. Inhibitors of the HATs involved may be of therapeutic value for the treatment of related leukemia (right).