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.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…Like TIP60 and MOF, human HBO1 is highly homologous to its counterpart in Drosophila (Hilfiker et al, 1997;Iizuka and Stillman, 1999;Smith et al, 2005;Mendjan et al, 2006). By contrast, MOZ and MORF only show sequence similarity to the very N-terminal region and MYST domain of Enok (Enoki mushroom), the most related Drosophila protein (Figures 1a and b) (Scott et al, 2001;Yang, 2004). Different from Drosophila, zebrafish possesses orthologs of MOZ and MORF (Figure 1c).…”

“…Within this program, histone acetyltransferases (HATs) play an integral role (reviewed in Sterner and Berger, 2000;Roth et al, 2001;Yang, 2004;Lee and Workman, 2007). As a pair of such enzymes, MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor) are important for different developmental programs and have been implicated in leukemogenic and other tumorigenic processes.…”

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

“…MOZ (MOnocytic leukemia Zinc-finger protein) (also called MYST3 or KAT6A) is a histone acetyltransferase (HAT) of the MYST (MOZ/YBF2/SAS2/TIP60 homology domain) family (Borrow et al, 1996b;Yang, 2004). In acute myeloblastic leukemia (AML), a chromosomal translocation fuses MOZ to a partner gene that can be CBP, p300, TIF2, NCOA3, or an unidentified one (Yang, 2004;Esteyries et al, 2008).…”

“…In acute myeloblastic leukemia (AML), a chromosomal translocation fuses MOZ to a partner gene that can be CBP, p300, TIF2, NCOA3, or an unidentified one (Yang, 2004;Esteyries et al, 2008). MOZ is a coactivator of various transcription factors particularly with hematopoietic specificity, such as RUNX1 (AML1) or Spi-1/ PU.1 (Kitabayashi et al, 2001;Katsumoto et al, 2006).…”

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

“…Dysregulated coactivator functions, resulting from chromosomal aberrations, in particular, have been suggested to promote oncogenesis (Anzick et al, 1997;Greaves and Wiemels, 2003;Yang, 2004). Examples include coactivators CBP/p300 and TIF2, which are associated with chromosomal translocations in leukemia as fusion proteins (Yang, 2004), and coactivators AIB1/SRC-3 and AIB3/TRBP, whose genes are amplified in breast cancers (Guan et al, 1996;Torres-Arzayus et al, 2004). Some oncoproteins have also been shown to have overlapping functions with coactivators (Brett et al, 1997), implicating the involvement of transcriptional coactivator actions in cancer development.…”