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MOZ and MORF, Two Large Mystic Hats in Normal and Cancer Stem Cells

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MOZ and MORF, Two Large Mystic Hats in Normal and Cancer Stem Cells Oncogene (2007) 26, 5408–5419 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells X-J Yang and M Ullah Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montre´al, Que´bec, Canada Genes of the human monocytic leukemia zinc-finger protein pattern. For cancer biology, it is thus important to MOZ (HUGO symbol, MYST3) and its paralog MORF understand the fundamental mechanisms whereby chro- (MYST4) are rearranged in chromosome translocations matin structure and function are regulated. In the associated withacute myeloid leukemia and/or benign past two decades, our knowledge about regulation in uterine leiomyomata. Both proteins have intrinsic histone this field has exploded. Known regulatory mechanisms acetyltransferase activity and are components of quartet include chromatin assembly, ATP-dependent remodeling, complexes withnoncatalytic subunits containing thebromo- covalent modification, condensin-mediated condensation, domain, plant homeodomain-linked (PHD) finger and replacement with histone variants, and association of proline-tryptophan-tryptophan-proline (PWWP)-containing noncoding RNA (reviewed by Horn and Peterson, 2002; domain, three types of structural modules characteristic of Khorasanizadeh, 2004; Li et al., 2007). Covalent chromatin regulators. Although leukemia-derived fusion pro- modification can occur at both the DNA and histone teins suchas MOZ-TIF2 promote self-renewal of leukemic levels. With histones, modifications include acetylation, stem cells, recent studies indicate that murine MOZ and phosphorylation, methylation, ubiquitination, and many MORF are important for proper development of hema- others (for reviews, see Spencer and Davie, 1999; Strahl topoietic and neurogenic progenitors, respectively, thereby and Allis, 2000; Berger, 2002; Jason et al., 2002; highlighting the importance of epigenetic integrity in Kouzarides, 2007). Different modifications interplay safeguarding stem cell identity. with each other and contribute significantly to the Oncogene (2007) 26, 5408–5419; doi:10.1038/sj.onc.1210609 formation of a complex epigenetic program for generat- ing and preserving the defined chromatin state of a given Keywords: lysine acetylation; MYST acetyltransferase; cell type. ING5; BR140; CBP; Runx1 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 Introduction (MOZ-related factor) are important for different devel- opmental programs and have been implicated in Like many other human diseases, cancer is a pathological leukemogenic and other tumorigenic processes. Here, condition with genetic and epigenetic basis (reviewed in we start with a brief overview about the discovery of this Baylin and Herman, 2000; Jaenisch and Bird, 2003; Egger pair and related acetyltransferases. We then summarize et al., 2004). Although genetic alteration is irreversible, molecular and genetic studies about this pair of HATs epigenetic changes are sometimes reversible. Diet, life- and discuss how their multiprotein complexes may act style, social interaction and environmental cues can as functional units to process molecular information trigger the reset of epigenetic programs, opening unique from histone methylation, phosphoinositides and other windows of opportunity for potential therapeutic inter- signaling cues for acetylation-based action in normal vention (for reviews, see Egger et al., 2004; Wade and and cancer stem cells. Archer, 2006; Nuyt and Szyf, 2007). How nuclear DNA is packaged into chromatin is a major epigenetic determinant. The specific chromatin organization in a given cell type (that is, the packaging state of nuclear Identification of MOZ, MORF and other MYSTic HATs DNA) is important for its unique gene expression pattern. A cancer cell may possess an aberrant chromatin The MOZ gene was initially identified as a fusion organization and thus an abnormal gene expression partner rearranged in the recurrent chromosome translocation t(8;16)(p11;p13) (Borrow et al., 1996). Independently, elegant genetic analysis in budding yeast Correspondence: Dr X-J Yang, Molecular Oncology Group, Royal Victoria Hospital, Room H5.41, McGill University Health Center, 687 identified Sas2 (something about silencing 2) and Pine Avenue West, Montre´ al, Que´ bec H3A 1A1, Canada. Sas3 as two homologous regulators of gene silencing E-mail: [email protected] (Reifsnyder et al., 1996). Sequence comparison revealed MOZ and MORF histone acetyltransferases X-J Yang and M Ullah 5409 that the three proteins display high sequence similarity their protein complex assembly, biochemical and within a B300-residue region with TIP60 (HIV Tat- biological function, and regulation. interactive protein of 60 kDa) (Kamine et al., 1996). The homologous region was named the MYST (MOZ, Ybf2/ Sas3, Sas2 and TIP60) domain (Borrow et al., 1996; MOZ and MORF as promiscuous transcriptional Reifsnyder et al., 1996). A putative acetyl-CoA-binding co-activators motif within the domain led to the hypothesis that these proteins are HATs. It was the time when the first few As shown in Figure 1b, MOZ and MORF are highly HATs were identified, so this hypothesis generated a homologous (overall amino-acid sequence identity, considerable amount of excitement. The hypothesis 60%; similarity, 66%), but only show homology to the received additional support from the discovery that a MYST domains of TIP60, MOF and HBO1. MOZ and mutation within the putative acetyl-CoA-binding motif MORF are large proteins (B250 kDa) and possess of Drosophila Mof (male-absent on the first), the fifth intrinsic HAT activity attributable to their MYST protein found to have the MYST domain, compromises domains (Champagne et al., 1999, 2001; Thomas et al., its crucial role in gene dosage compensation (Hilfiker 2000; Kitabayashi et al., 2001a). Both histones H3 and et al., 1997). TIP60 and yeast Esa1 (essential Sas2- H4 are the substrates in vitro. Analysis of recombinant related acetyltransferase 1) were then demonstrated MORF proteins, expressed in and affinity-purified from to possess intrinsic HAT activity (Yamamoto and insect cells, indicates that the full-length protein is more Horikoshi, 1997; Smith et al., 1998). HBO1 (HAT active than the MYST domain alone (Champagne et al., bound to ORC1) was identified as a binding partner of 1999; Pelletier et al., 2003), suggesting that the HAT ORC1 (replication origin complex 1) (Iizuka and Still- activity is regulated by other domains or association man, 1999). BLAST search against expressed sequence with other proteins. Both MOZ and MORF are tag databases for additional MYST proteins led to the autoacetylated (Champagne et al., 1999), with one identification of human MORF as a MOZ paralog acetylation site located C terminus to the MYST (Champagne et al., 1999), and murine MORF was domain (Kim et al., 2006). But the functional signifi- identified independently as Querkopf (Thomas et al., cance of this modification remains to be determined. 2000). As shown in Figure 1b, other protein domains of There are three MYST proteins in budding yeast and MOZ and MORF include an NEMM (N-terminal five in Drosophila or humans (Figure 1). Notably, the part of Enok, MOZ or MORF) domain, tandem PHD MYST domain is the only structural feature common to (plant homeodomain-linked) zinc fingers, a long acidic all members of this family. Metazoan TIP60 proteins are stretch, and an SM (serine/methionine-rich) region. The orthologous to Esa1 owing to similar domain organiza- C-terminal part of the NEMM domain shows some tion, complex formation and cellular function (Doyon sequence similarity to histones H1 and H5, but the and Coˆ te´ , 2004). At the functional level, metazoan MOF function of this domain is not that clear. The H15-like proteins are somewhat similar to Sas2 (Rea et al., 2007). domain was shown to promote nuclear targeting Like TIP60 and MOF, human HBO1 is highly homo- (Kitabayashi et al., 2001a). The tandem PHD fingers logous to its counterpart in Drosophila (Hilfiker et al., are similar to those of Requiem and homologs (Figure 1) 1997; Iizuka and Stillman, 1999; Smith et al., 2005; (Borrow et al., 1996; Nabirochkina et al., 2002). Mendjan et al., 2006). By contrast, MOZ and MORF Requiem is part of an interaction network controlling only show sequence similarity to the very N-terminal pluripotency of embryonic stem cells (Wang et al., region and MYST domain of Enok (Enoki mushroom), 2006). These fingers may have important function. One the most related Drosophila protein (Figures 1a and b) possibility is to recognize methyl-lysine-containing (Scott et al., 2001; Yang, 2004). Different from motifs (Kouzarides, 2007). Drosophila, zebrafish possesses orthologs of MOZ and The SM domain possesses transcriptional activation MORF (Figure 1c). Thus, different from TIP60, MOF and potential, so it was hypothesized that MOZ and MORF HBO1, both MOZ and MORF are vertebrate-specific. are transcriptional coregulators (Champagne et al., The MYST family of HATs was not as widely studied 1999, 2001). Indeed, they interact with Runx proteins as Gcn5/PCAF and p300/CBP, but this situation has and activate transcription (Kitabayashi et al., 2001a; changed greatly in the past few years. It is now known Pelletier et al., 2002; Bristow and Shore, 2003; Kindle that
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