Oncogene (2007) 26, 5373–5384 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW MYST opportunities for growth control: yeast illuminate human cancer functions

A Lafon, CS Chang, EM Scott, SJ Jacobson and L Pillus

Section of Molecular Biology, Division of Biological Sciences, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

The MYST family of acetyltransferases (HATs) genes were identified with potential roles in chromatin- was initially defined by human genes with disease mediated gene control, even modest degrees of similarity connections and by yeast genes identified for their role to the acetyl-CoA-binding regions were viewed with in epigenetic transcriptional silencing. Since then, many special interest as candidate HATs. new MYST genes have been discovered through genetic Such interest was particularly the case when mutants and genomic approaches. Characterization of the com- of SAS2 (something about silencing) were discovered as plexes through which MYST act, regions of enhancers of mutations in the epigenetic transcriptional the genome to which they are targeted and biological silencer factor Sir1 (Reifsnyder et al., 1996) and consequences when they are disrupted, all deepen the suppressors of defects in cis-regulatory sequences for connections of MYST proteins to development, growth silent chromatin (Reifsnyder et al., 1996; Ehrenhofer- control and human cancers. Many of the insights into Murray et al., 1997). The observation that SAS2 and the MYST family function have come from studies in model closely related SAS3 yeast genes shared similarity to organisms. Herein, we review functions of two of the acetyl-CoA-binding domains, and even more significant founding MYST genes, yeast SAS2 and SAS3, and the similarity to two human genes, MOZ (Borrow et al., essential yeast MYST ESA1. Analysis of these genes in 1996) and TIP60 (Kamine et al., 1996), quickly led to yeast has defined roles for MYST proteins in transcrip- the recognition that together these genes defined a tional activation and silencing, and chromatin-mediated broadly conserved family that was named MYST for its boundary formation. They have further roles in DNA founding members (MOZ-YBF2/SAS3-SAS2-TIP60) damage repair and nuclear integrity. The observation that (Borrow et al., 1996; Reifsnyder et al., 1996). ESA1 MYST complexes share subunits with other HATs, was later identified as the third yeast MYST gene (Smith histone deacetylases and other key nuclear proteins, et al., 1998a; Clarke et al., 1999) with diverse functions: many with connections to human cancers, strengthens the it is essential for viability, and plays roles in transcrip- idea that coordinating distinct chromatin modifications tional activation, silencing, cell cycle progression and is critical for regulation. DNA damage repair. Oncogene (2007) 26, 5373–5384; doi:10.1038/sj.onc.1210606 The MYST domain – defined as the most conserved region in MYST family proteins – comprises a region Keywords: chromatin; transcription; Saccharomyces that includes both the sequences surrounding the acetyl- cerevisiae; silencing CoA-binding domain and in most enzymes an atypical C2HC zinc finger. Whereas the sequence of the MYST core domain is well conserved in Sas3 and Sas2, Esa1 lacks three of the four amino acids for zinc binding. Overview However, the crystal structure of Esa1 revealed that this region forms a classical TFIIIA-type zinc finger fold in Among the many chromatin modifications known, the absence of zinc suggesting a structurally conserved histone received particularly prominent early core domain with other MYST HATs (Yan et al., 2000). attention with the molecular identification of HAT1 and Besides the MYST domain, Sas3 and Esa1 contain GCN5 as genes encoding histone acetyltransferases additional conserved regions that are only found in (HATs) (Kleff et al., 1995; Brownell et al., 1996; subsets of the MYST family proteins, described below. Parthun et al., 1996). Although these two HATs have The early link between human MOZ, a recurrent different substrate specificities, initial sequence compar- translocation partner in several acute leukemias, and the isons revealed significant yet restricted similarity in three yeast genes implicated in chromatin-mediated regions predicted to bind acetyl-CoA. When additional transcriptional silencing raised the possibility that fundamentally conserved mechanisms might inform basic understanding between silencing mechanisms and Correspondence: Dr L Pillus, Section of Molecular Biology, Division of Biological Sciences, UCSD Moores Cancer Center, University of human disease. As further genomic and genetic analyses California, San Diego, La Jolla, CA 92093-0347, USA. proceeded, it became clear that the MYST family was E-mail: [email protected] broadly conserved. As of early 2007, several hundred Yeast MYST HATs and human cancer A Lafon et al 5374 related genomic sequences sharing significant sequence Here, their structural and functional distinctions are similarity over an B150 amino acid domain encompass- briefly highlighted in three categories: (1) definitions ing the acetyl-CoA-binding site have been annotated as of histone substrate specificity À of particular interest MYST genes (http://www.ncbi.nlm.nih.gov/entrez/query. are disease-relevant non-histone substrates such as fcgi?db ¼ Protein). Among MYST proteins of particular in humans (Sykes et al., 2006; Tang et al., 2006), note are the Drosophila MOF gene that is essential only in (2) the MYST multi-protein complex(es) that modulate males for dosage compensation (Hilfiker et al., 1997) and enzymatic activity and promote coregulation with other the human MOF, MORF, MOZ and HBO1 genes that chromatin remodeling complexes through shared sub- have been implicated in multiple aspects of human units and (3) the gene-specific versus global acetylation development and disease (Avvakumov and Coˆ te´ ,2007; patterns that are of critical importance for disease and Rea et al., 2007). assessing potential success and side effect of therapeutic Many insights into MYST gene functions came initi- agents. These aspects are considered in more detail in ally from studies in model organisms, including Droso- other recent reviews (Utley and Coˆ te´ , 2003; Yang, 2004; phila, Caenorhabditis elegans, mouse, and the yeasts Altaf et al., 2007). We go on to address yeast MYSTs in Saccharomyces pombe and Saccharomyces cerevisiae the context of human disease, illustrated by mutant (described elsewhere in this issue and reviewed in Yang, phenotypes and conserved complex subunits. Further, 2004). This progress has come from the open-ended we consider what has been learned from genomic and nature of genetic screens, targeted gene deletion tech- proteomic surveys in yeast and speculate on what may niques and biochemical approaches combined with be learned from future studies that will be relevant for complete genome sequences and resources. understanding human health and disease. S. cerevisiae is a particularly rapid and informative genetic system for dissecting human protein function. For example, two-hybrid screening identified an inter- SAS3: critical functional links to GCN5 and H3 action of the MYST protein HBO1 with progesterone modifications receptor (PR) (Georgiakaki et al., 2006), a member of the family of steroid receptors. This observation SAS3 is arguably the least well-understood MYST gene prompted further analysis in human cells, which showed in yeast. In large part, this is because of the lack of that HBO1 enhancement of PR-dependent transcription extreme phenotypes observed upon deletion; indeed, required steroid receptor coactivator SRC-1 (Georgia- SAS3 was originally reported to have only minor kaki et al., 2006). Steroid receptors and their coactiva- functions in silencing at mating-type loci (Reifsnyder tors are key regulators of gene expression (Lonard and et al., 1996). O’Malley, 2006) and participate in signaling pathways Sas3 contains extensive stretches of acidic aspartate susceptible to misregulation in cancer cells. Yeast assays and glutamate residues in its C-terminus region, also can be designed also to study mechanisms of coactivator found in the human MYST HATs MOZ and MORF. function. For example, phenotypes conferred upon Although the functional significance of this domain in expression of hSRC-3 (Brown et al., 2003), GRIP1 the human proteins remains unclear, the acidic domain and SRC-1 (Anafi et al., 2000) revealed a role for Gcn5 of Sas3 is required for its physical interaction with the HAT complex components. These and other ingenious essential transcriptional elongation factor Spt16 through yeast assays will lend further insight into mechanisms two-hybrid screening (John et al., 2000). This suggests a underlying human MYST HAT function. The clinical function of Sas3 in transcriptional regulation mediated implications of these observations can be further tested by RNA polymerase II. in yeast screens to identify chemicals that interact with Although much remains to be learned of the biological steroid hormones and coactivators to modulate their processes regulated by SAS3, the determinants of its transcriptional output (Nishikawa et al., 1999) and molecular function have been well characterized, correlate mutations in key cancer-associated proteins including the multi-protein complex containing Sas3 with mutations that are clinically relevant, as was and the histone residues it targets. Sas3 is the catalytic the case with p53 mutant screens in yeast (Brachmann subunit of the large multi-protein complex named NuA3 et al., 1996). (for Nucleosomal Acetylation of H3) (John et al., 2000). An underlying principle of screening human protein This complex (Figure 1 and Table 1) contains the Sas3 function in yeast is that their function is conserved. enzyme plus four subunits clearly identified as stable Recent advances defining human MYST complexes components: (1) the TBP-associated factor Taf14; (2) underscore this conserved molecular nature (Avvaku- the Yeast iNhibitor-of-Growth protein Yng1; (3) Eaf6, mov and Coˆ te´ , 2007) that is often mirrored in conserved first identified as an Esa1-associated factor and (4) the function. Although yeast has a simpler MYST repertoire NuA Three ORF, Nto1 (John et al., 2000; Howe et al., than humans, it is likely that ongoing studies will 2002; Doyon et al., 2004; Krogan et al., 2006; Taverna continue to identify additional histone and non-histone et al., 2006). Of note, two of these NuA3 components are substrates, mechanisms for regulation and, ultimately, shared by other complexes whose function is linked pharmacological modulators with therapeutic signifi- to chromatin (a feature observed for other NuA4 cance. (Nucleosomal Acetylation of H4) complex components In this review, we begin by considering each of the whose catalytic subunit is Esa1, see below): Taf14 is also S. cerevisiae MYST genes and proteins individually. a component of the transcription-related complexes

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5375 Two recent papers provided new insight on the molecular function of the NuA3 complex, and further uncovered a specific role of the NuA3 complex compo- nent, Yng1 (Martin et al., 2006; Taverna et al., 2006). A previous study established that Yng1 is required for NuA3 function by promoting interaction of Sas3 with nucleosomes (Howe et al., 2002). The recent studies further characterized this interaction to show that Yng1 binds nucleosomes that have been methylated by Set1 and Set2 at H3-K4 and H3-K36, respectively (Martin et al., 2006; Taverna et al., 2006). Furthermore, it was observed that Yng1 binding promotes NuA3 HAT activity at K14-targeted genes. These results and the B Figure 1 The NuA3 complex. NuA3 is a 450 kDa complex that enrichment of H3-K4me3 at the 50 end of transcription- acetylates lysine residues on histone H3. The NuA3 complex is not yet fully characterized, and contains at least five known subunits, of ally active open reading frames (Pokholok et al., 2005) which Sas3 (in yellow) is the catalytic HAT. At least three of the support a role for NuA3 in transcriptional activation. five subunits of NuA3 are related to human oncogenes or tumor suppressors and are further described in Table 1. Subunits are categorized as: Level 1, human homologs that are mutated in cancers; Level 2, associated with cellular processes commonly SAS2: distinct functions at chromatin-mediated barriers defective or inactivated in cancer cells, such as cell cycle regulation for heterochromatin and DNA damage repair. HAT, histone acetyltransferase. Compared with SAS3, more studies have focused on SAS2 as its deletion results in several clear effects on transcriptional silencing (Reifsnyder et al., TFIID, TFIIF, INO80, mediator and SWI/SNF 1996; Ehrenhofer-Murray et al., 1997; Meijsing and complexes; Eaf6 is part of the NuA4 complex (Nourani Ehrenhofer-Murray, 2001). In addition to phenotypic et al., 2001). Although several other potential NuA3 differences in the mutants, Sas2 also differs in its histone components have been identified by mass spectrometry substrate specificity, HAT-associated multi-protein (John et al., 2000), their validation awaits further complexes and the cellular processes it regulates. study. Sas2 is the catalytic subunit of the SAS complex that The characterization of the enzymatic activity of Sas3 also includes Sas4 and Sas5 (Meijsing and Ehrenhofer- – as a purified recombinant protein as well as part of the Murray, 2001; Osada et al., 2001; Sutton et al., 2003) NuA3 complex in vitro and in vivo – established HAT (Figure 2 and Table 1). The acetyl-CoA-binding domain activity toward histone H3 (Takechi and Nakayama, of Sas2 is essential for the enzymatic activity of the SAS 1999; John et al., 2000; Howe et al., 2001). Furthermore, complex, in which deletion or mutations produce the lysine 14 of histone H3 (H3-K14) was identified as same phenotype (Meijsing and Ehrenhofer-Murray, the primary substrate of the NuA3 complex in vitro 2001; Osada et al., 2001). Sas4 is required for HAT and in vivo (Howe et al., 2001), and of note, this is activity of Sas2, whereas Sas5 increases HAT activity also a preferred substrate of Gcn5 (Baker and Grant, in vitro, although is not essential for complex function 2007). (Sutton et al., 2003). Additional clues about the biological function of Sas3 In contrast to NuA3, in vitro experiments show that are provided by the synthetic lethal interaction between the SAS complex acetylates at K16 and mutants of SAS3 and GCN5 (Howe et al., 2001). Gcn5 is contributes extensively to the bulk of H4-K16 acetyla- a member of the GNAT family of acetyltransferases and tion in vivo (Kimura et al., 2002; Shia et al., 2006). In shares overlapping patterns of acetylation with Sas3. parallel, mutation of H4-K16 mimics sas2D phenotypes Simultaneous disruption of SAS3 and GCN5 is synthe- (Meijsing and Ehrenhofer-Murray, 2001). Whereas Sas3 tically lethal due to the loss of acetyltransferase activity. and Sas2 have the same role in HMR mating-type This synthetic lethal interaction establishes that histone transcriptional silencing, early studies on Sas2 function H3 acetyltransferase activity contributes to viability in uncovered a more significant role promoting silencing yeast, and builds on earlier mutational studies demon- at HML and telomeres (Reifsnyder et al., 1996; strating critical, yet perhaps redundant roles for acetyl- Ehrenhofer-Murray et al., 1997; Xu et al., 1999b). ation of either H3 or H4 tails (reviewed in Grunstein, The mechanism of Sas2 function in telomeric silencing 1990). Furthermore, loss of GCN5 combined with reveals a crucial role in establishment of silencing several mutant alleles of SAS3, including deletion of barriers in concert with the histone deacetylase (HDAC) the aspartate/glutamate C terminus, results in condi- Sir2 (Kimura et al., 2002; Suka et al., 2002). The two tional arrest in the G2/M phase of the cell cycle, proteins oppose each other in H4-K16 acetylation to demonstrating a role for Sas3 in cell cycle regulation. establish a modification gradient along the chromo- In support of such a function, Sas3 has been reported to some, from a hypo-acetylated state at the telomeres to a physically interact with the Chk1 DNA-damage effec- hyper-acetylated state in more distal regions. The tor kinase that mediates mitotic cell cycle arrest establishment of this barrier requires both H4-K16 (Liu et al., 2000). acetylation and deacetylation activities mediated by

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5376 Table 1 MYST complexes and connections to disease NuA3 Description/disease connection Yeast mutant

Eaf6 Homolog found in human ING complex (Doyon et al., 2006) Viable Nto 1 Similar to human Jade and BRPF, which interact with tumor Viable suppressors Sas3 Catalytic subunit, similar to MOZ and MORF Synthetic lethal with GCN5, increased yeast transcriptional activation by heterologously expressed p53 Taf14/ YEATS domain containing protein, part of TFIID, TFIIF, INO80, Sensitive to caffeine and DNA-damaging agents HU, MMS Taf30 mediator and SWI/SNF complexes and UV Yng1 Homolog of human ING tumor suppressor proteins Viable, increased yeast transcriptional activation by heterologously expressed p53

SAS Description/disease connection Yeast mutant

Sas2 Catalytic subunit, similar to HBO1 and MOF Defective in silencing Sas4 Required for activity of Sas2 Defective in silencing (Xu et al., 1999a, b) Sas5 YEATS domain, similar to leukemogenic proteins Defective in silencing (Xu et al., 1999a, b)

NuA4 Description/disease connection Yeast mutant

Act1 Actin, part of SWR1 and IN080 complexes Inviable Arp4 Actin-related protein, binds phosphorylated H2A-S129 during Inviable, conditional mutants sensitive to HU and UV DNA damage, part of SWR1 and IN080 complexes Eaf1 Esa1-associated factor Viable Eaf3 Esa1-associated factor, part of Rpd3 histone deacetylase complex Viable (Carrozza et al., 2005; Keogh et al., 2005), Drosophila homolog is dosage compensation protein MSL3 (Eisen et al., 2001) Eaf5 Esa1-associated factor Viable Eaf6 Homolog found in human ING complex (Doyon et al., 2006) Viable Eaf7 Esa1-associated factor Viable Epl 1* Homolog of Drosophila Enhancer of Polycomb Inviable, conditional mutant is defective in cell cycle progression Esa 1* Catalytic subunit, homolog of human Tip60, involved in cell cycle Inviable, conditional mutants sensitive to topoisomerase progression inhibitor CPT and MMS, defective in silencing Swc4/Eaf2 Part of SWR1 complex (Krogan et al., 2004) Inviable Tra1 Homolog of TRAAP, which is required for oncogenic Inviable transformation, involved in DNA repair (ATM-related), regulation of Pol II transcription Yaf9 YEATS domain, similar to leukemogenic proteins, part of SWR1 Sensitive to HU, MMS, UV and other DNA-damaging complex agents, and spindle stress Yng2* Homolog of human ING tumor suppressor proteins Sensitive to CPT, HU and MMS, required for yeast transcriptional activation by heterologously expressed p53

Abbreviations: CPT, camptothecin; HU, hydroxyurea; MMS, methyl methanesulfonate; UV, ultraviolet radiation. Subunits are listed alphabetically within each complex, and those with direct disease parallels (Level 1 in Figures 1–3) are highlighted in bold. The piccolo subunits are marked with an * in the NuA4 section. Relevant phenotypes of yeast mutants are noted and are further described and referenced at Saccharomyces Genome Database (www.yeastgenome.org). Listed references are restricted to those not already mentioned in the text.

Sas2 and the HDAC Sir2, respectively (Kimura et al., 2002; Suka et al., 2002). In addition, the HAT activity of SAS in sub-telomeric regions is required for efficient H2A.Z incorporation near telomeres. The presence of H4-K16 acetylation and H2A.Z synergistically prevent the ectopic propagation of heterochromatin into transcriptionally active regions (Shia et al., 2006). A key function of the SAS complex is also medi- ated through replication-coupled chromatin assembly. Indeed, physical and genetic interactions have been Figure 2 The SAS complex. The SAS complex is the smallest of the MYST complexes in yeast, and at 125 kDa is composed of three established between the SAS complex and two chroma- subunits. Sas2 (in yellow) is the catalytic subunit, whereas Sas4 and tin assembly factors Asf1 and Cac1, suggesting that Sas5 are important for specificity, complex integrity and optimal the SAS complex is recruited to freshly replicated DNA activity. Sas5 contains a YEATS domain, found in human to acetylate H4-K16 during assembly (Meijsing leukemogenic proteins. All of these subunits are further described in Table 1. Levels 1 and 2 are as defined in Figure 1; Level 3 disease and Ehrenhofer-Murray, 2001; Osada et al., 2001). This associations have not yet been characterized, but mutant pheno- interaction seems to be particularly important for types and functions provide clues for future study. silencing at the cryptic HM mating-type loci as the

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5377 ASF1-dependent localization of the SAS complex is required for SIR1-dependent HML silencing (Osada et al., 2001). In addition to these chromatin assembly factors, the origin recognition complex (ORC) that is essential for DNA replication appears to be a key element for the establishment of silencing at mating- type loci mediated by Sas2. This link was defined by interactions between Sas2 and the ORC proteins Orc2 and Orc5 in the establishment of transcriptionally repressed chromatin (Ehrenhofer-Murray et al., 1997). The requirement for the ORC complex in promoting silencing appears to be independent of its replicative role (Kirchmaier and Rine, 2001; Li et al., 2001) and is still being defined mechanistically. In sum, study of Sas2 reveals an intriguing function in maintaining heterochromatin boundaries that demar- Figure 3 The NuA4 complex. The NuA4 complex is 1.3 MDa and contains six subunits that are essential for viability (shown as bold cate specialized silenced regions of chromatin from outline), with Esa1 (in yellow) as the catalytic HAT. Many of the those that are transcriptionally active. This function components are related to human disease genes and are present in involves physical and genetic interactions with other other chromatin modification complexes. Piccolo is a distinct Esa1 chromatin-related complexes/proteins, the HDAC complex containing a subset of three NuA4 subunits. The piccolo Sir2, the chromatin assembly factors Asf1 and Cac1, subunits are underlined. Levels 1–3 are as defined in Figures 1 and 2. These subunits are further described in Table 1. and the ORC complex. Although not yet reported, similar boundary functions may be dependent on MYST protein complexes in humans, since many of the factors are themselves conserved and maintenance of hetero- complex that deposits the Htz1 histone variant into chromatic and euchromatic regions is an integral part of chromatin (Krogan et al., 2003, 2004; Kobor et al., human development and gene regulation. 2004). Moreover, NuA4 shares Tra1 with two Gcn5- contining HAT complexes, SAGA and SLIK. In both the SAGA and NuA4 complexes, Tra1 targets the HAT ESA1: an essential MYST linking essential complexes to their proper promoter-specific sites of acety- cellular processes lation through physical interactions with transcription activators (Brown et al., 2001). Several key distinctions set ESA1 apart from the other Among the MYST complexes, NuA4 displays exten- yeast MYST genes. These include the essential nature ded histone substrate specificity as it acetylates prefer- of ESA1 and the large spectrum of cellular processes entially H4 and H2A on nucleosomal templates it regulates, described below. Another key feature is (Allard et al., 1999). In vitro experiments with recombi- that Esa1 is the catalytic subunit of two distinct multi- nant Esa1 demonstrates activity on H4, H3 and H2A protein complexes: NuA4 and piccolo (Figure 3 and core histones (Smith et al., 1998a; Clarke et al., 1999); Table 1). in vivo Esa1 is responsible for much of H4-K5 acetyla- NuA4 is the largest MYST complex in yeast, contain- tion (Clarke et al., 1999). On promoters of candidate ing Esa1 and 12 other subunits. Among the best genes, Esa1 acetylates all sites tested on H4, H2A and characterized components of the NuA4 complex are H2B tails, except H4-K16 (Suka et al., 2001). NuA4 also Tra1, the essential ATM-family cofactor that facilitates mediates acetylation of H2A.Z after its incorporation by recruitment of NuA4 (Allard et al., 1999; Brown et al., the SWR1 complex (Babiarz et al., 2006; Keogh et al., 2001); Yng2, an inhibitor-of-growth 1 (ING1) tumor 2006; Millar et al., 2006). suppressor homolog, involved in cell cycle progression The essential nature of Esa1 illustrates the critical and DNA-damage response (Choy et al., 2001; Choy functions performed by this MYST protein in numerous and Kron, 2002); Arp4, an essential actin-related protein chromatin-dependent processes (Smith et al., 1998b; with roles in gene-specific transcription regulation Clarke et al., 1999). Indeed, Esa1 plays a crucial role (Galarneau et al., 2000); and Epl1, an essential homolog in cell cycle progression through G2/M as an esa1 of the Drosophila Enhancer of Polycomb, involved in conditional mutant proceeds through DNA replication cell cycle progression through G2/M (Boudreault et al., but fails to complete mitosis and cytokinesis (Clarke 2003). The piccolo complex is a subset of the NuA4 et al., 1999). This arrest is dependent on the RAD9- complex with very high HAT activity toward nucleo- mediated DNA damage checkpoint as RAD9 deletion somes that consists of three subunits, Esa1, Yng2 and prevents esa1 mutant G2/M arrest, but does not Epl1 (Boudreault et al., 2003). significantly affect loss of viability, suggesting additional As described above for the NuA3 complex, several roles for Esa1. One mechanism underlying these components of NuA4 are shared with chromatin-related phenotypes is that acetylation of histone H4 by Esa1 complexes. Arp4 is present in the INO80 chromatin is required for DNA double-strand break repair (Bird remodeling complex (Shen et al., 2003) and along with et al., 2002). Moreover, the NuA4 subunit Arp4 is two other subunits, Yaf9 and Act1, is part of the SWR1 recruited in vivo to the site of DNA double-strand

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5378 breaks (Bird et al., 2002; Downs et al., 2004). Esa1 2005). The CHD function is not yet clearly defined in itself localizes to DNA double-strand breaks as well the human MYST proteins, although many CHDs (Tamburini and Tyler, 2005). appear to bind methylated histones (reviewed in Daniel Esa1’s function in transcriptional activation has been et al., 2005). Like Esa1, Tip60 has clear roles in studied at a genome-wide level and with individual transcriptional activation and silencing, and distinct target gene validation (Reid et al., 2000), revealing a functions in DNA damage and repair (Avvakumov and clear role in transcription of growth-essential ribosomal Coˆ te´ , 2007). protein genes. In addition to promoting transcription, But what of Sas2 and Sas3? Identification of human Esa1 also functions in telomeric and rDNA silencing orthologs is somewhat less direct because neither yeast (Clarke et al., 2006). Indeed, Esa1 is important for enzyme has a strikingly similar combination of other maintaining nucleolar structure as revealed by altered domains, such as paired PHD (Plant HomeoDomain) localization of Nop1 and Sir2 nucleolar proteins and boxes, or H15 domains that characterize some of the differences in pulsed-field gel electrophoresis of chromo- human proteins. However, several features of each yeast somes and ultrastructural profiles in esa1 mutants protein ally them with distinct human MYSTs. Sas3 has (Clarke et al., 1999, 2006). Like Sir2, Esa1 is enriched the longest C-terminus extension flanking the MYST at rDNA and both mutants are defective in rDNA domain, and like MOZ and MORF, this region is silencing. In contrast to sir2D, esa1 loss of function notably aspartate and glutamate rich. Sas3 has a marked slightly increases the recombination rates in rDNA. preference for H3 acetylation, whereas the human The overexpression of ESA1 can bypass the requirement proteins acetylate both H3 and H4. In contrast to the for Sir2 in rDNA silencing, suggesting that these dearth of sas3 null phenotypes, recurrent reciprocal two proteins with opposing enzymatic activities both translocations of MOZ or MORF to chromatin-modi- contribute to proper nucleolar structure and function fying genes including CBP, p300 and TIF2 occur in (Clarke et al., 2006). patients with acute myeloid leukemia (AML). Both A genome-wide analysis of Esa1 occupancy in yeast in vitro and in vivo studies indicate that the fusion revealed that this MYST protein is generally recruited to proteins arising from these translocations are the the promoters of active protein-encoding genes (Robert causative agent of cancer, apparently by interfering et al., 2004), which correlates well with earlier studies with the activities of key regulatory proteins including (Reid et al., 2000). Several candidate target genes have nuclear receptors, the tumor suppressor p53 and Runx been examined in detail. For example, Esa1 was shown proteins (reviewed in Yang, 2004; Troke et al., 2006). to occupy and acetylate the PHO5 promoter, resulting Sas2 also shares similarities with more than one in transcriptional activation (Vogelauer et al., 2000; human MYST. Sas2 HAT activity is restricted to H4, Nourani et al., 2004). similar to the human MOF, and BLAST sequence analysis of yeast Sas2 with default settings returns hMOF as the top hit. Studies of MOF in Drosophila The MYST HATs: yeast answers and cancer insights have revealed an important enzymatic role in the male specific lethal (MSL)-containing dosage compensation The individual summaries above of each yeast MYST complex. MOF increases H4-K16 acetylation and HAT and the complex(es) through which they act high- transcription of the single male X (Hilfiker light the fundamental, and likely conserved functions for et al., 1997; Smith et al., 2000). A human MSL-like the family of enzymes. How can this information help us complex containing hMOF has been identified and think about cancers in humans that may be influenced functions in cell cycle progression (Smith et al., 2000). It by acetylation and other processes controlled by MYST will be interesting to see how this function is related to proteins? A starting point for the answer to this question the hMOF interaction with ATM, a protein important comes from the enzymes themselves and their conserved in DNA damage responses (Gupta et al., 2005). complex subunits that have been correlated with various Sas2 also shares conserved interacting partners with pathologies and developmental defects in metazoans. the human MYST HBO1 that manifest in different phenotypes at the organismal level (Avvakumov and Coˆ te´ , 2007). Perhaps Sas2 melds features and functions Correlating yeast and human MYSTs of both MOF and HBO1, as appears to be the case for the S. pombe mst2 þ (Go´ mez et al., 2005) when By both molecular architecture and sequence identity, compared to S. cerevisiae Sas2 and Sas3. Esa1 appears most closely related to the human Tip60 Also of note are Sas2’s functional interactions with protein because of their overall structures. This includes members of the ORC replication complex (Ehrenhofer- the shared N-terminus chromodomains (CHDs), the Murray et al., 1997; Meijsing and Ehrenhofer-Murray, MYST domain itself and considerable sequence simi- 2001) and postreplication chromatin assembly factors larity throughout the remainder of the two proteins. (Osada et al., 2001). These are paralleled by interactions Esa1 is the only yeast MYST to possess a CHD, also of human HBO1 with ORC (Iizuka and Stillman, 1999). found in human and Drosophila MOF. In dMOF, the Whereas the Sas2 and replication protein interactions CHD contributes to RNA binding (Akhtar et al., 2000), underlie epigenetic regulation of gene expression in and in Esa1 is critical for growth and some aspect yeast, HBO1 interactions seem more clearly tied to repli- of catalysis after nucleosome binding (Selleck et al., cation origin function. One of the earliest observations

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5379 that revealed this important link to cell proliferation was enzyme, the histone methyltransferase Dot1 (Zhang that HBO1 associates with both hORC1 (Iizuka and et al., 2006). Although interaction with yeast Dot1 has Stillman, 1999) and MCM2 (Burke et al., 2001) in not yet been reported for Taf14, Sas5 or Yaf9, it appears mammalian cells and may be important in forming a that a role in histone modification for YEATS domain functional replication complex (Iizuka and Stillman, proteins is conserved. 1999; Iizuka et al., 2006). Furthermore, HBO1 interacts Taf14 is the YEATS protein in NuA3, and is a with ING4 and ING5 (Doyon et al., 2006), and CDK11 component of multiple chromatin-modifying complexes, (Zong et al., 2005) to regulate cell cycle progression. as noted above. Mutant taf14D cells are sensitive to Although human cancers directly implicating HBO1 DNA-damaging agents (Cairns et al., 1996; Kabani have not been reported, this area of research will be et al., 2005). Like yeast Taf14, human GAS41 (glioma important in understanding fundamental mechanisms of amplified sequence 41, also known as YEATS4) is cell cycle control that have gone awry in cancers, in reported to interact with INI1, the human homolog of addition to HBO1’s known involvement in gene expres- Snf5, a subunit of the SWI/SNF complex (Debernardi sion through interaction with transcription factors et al., 2002). This is another example of conserved roles (Sharma et al., 2000; Sterner and Berger, 2000). for YEATS proteins. Sas5, the YEATS domain-containing member of the SAS complex (Xu et al., 1999a; Osada et al., 2001), is Parallels in MYST complexes essential for complex integrity and HAT activity (Xu et al., 1999b; Osada et al., 2001; Shia et al., 2005). It has In defining the yeast MYST complex subunits above, been suggested that YEATS domain proteins may play a note was made of similar subunits shared among them. role in targeting their complexes to chromatin bound- Equally striking are the number of subunits with human aries (Zhang et al., 2004), a model which if correct homologs that are themselves associated with specific would explain why they are often found associated with human cancers and/or tumor suppressors. This point is silencing or anti-silencing factors. highlighted by the color scheme for the complexes in Yaf9, a component of NuA4, was named for its Figures 1–3, in which noncatalytic subunits with human similarity to the AF-9 human leukemogenic protein homologs are shaded to denote different levels of disease although it is now recognized to be more similar to association. Some MYST complex members have GAS41 (Le Masson et al., 2003). Mutant YAF9 obvious homologs that are specifically related to a type phenotypes suggest a role in DNA repair (Bittner of cancer, whereas others have roles in processes that are et al., 2004; Zhang et al., 2004) and Yaf9 is also part defective in cancers, such as DNA damage repair, and of the SWR1 complex (Kobor et al., 2004; Krogan et al., cell cycle control (Table 1). 2004). Yaf9 binds to Swc4, a NuA4 and SWR1 com- Many members of the yeast MYST complexes are plex component that is the homolog of mammalian conserved in mammals, establishing a link between the DNA methyltransferase-associated protein 1, DMAP1 human proteins and the transcriptional activation (Doyon et al., 2004). function of the yeast proteins. It should be noted that Aside from the YEATS proteins, there are several there is both conservation of individual subunits from other yeast MYST complex members that share yeast to humans, and that the whole complex appears homology to cancer-related genes. Whereas some of conserved. When mutated, many of these human these have homology with potential oncogenes, others proteins become oncogenic (Ogryzko, 2001; Timmer- resemble human tumor suppressors. The NuA4 subunit mann et al., 2001). Indeed, studies of yeast chimeric Yng2 and the NuA3 subunit Yng1 share homology with proteins mimicking the MOZ translocation fusion the human ING tumor suppressor family. partners found in some AML patients show that they Studies by Nourani and colleagues use human p53 can misregulate gene expression upon aberrant chro- expressed in yeast cells to examine the effect of yeast mosomal targeting (Jacobson and Pillus, 2004). Thus, MYST genes on p53’s function as a transcriptional further analysis of the yeast phenotypes may become activator. Both human and yeast ING homologs can even more informative in dissecting the mechanisms modulate p53 activity. Yng2 is the yeast homolog of the underlying oncogenesis. human Ing1/p33 tumor suppressor, and is required for There are three YEATS domain (defined by the first p53-dependent transcription (Nourani et al., 2001). This proteins in which it was found (Yaf9-Enl-AF9-Taf14- demonstrates the broad functional conservation of the Sas5)) proteins in yeast: Taf14, Sas5 and Yaf9, each of ING proteins from yeast to humans. Since p53 has which participates in a distinct MYST complex. functions in both transcriptional activation and DNA Although each individual null mutant is viable, deleting damage response, there may be many further connec- all three genes results in cell death, demonstrating that at tions between p53 and histone-modifying complexes. least one domain is essential (Zhang et al., 2004). Human Human p53 interacts with NuA4 in vivo in yeast cells proteins with YEATS domains include Enl and AF-9, (Nourani et al., 2001), just as p53 interacts with ING1 in dysfunction of which is associated with leukemias human cells. p53 is acetylated by the human Tip60 H4/ (reviewedinZhangandRowley,2006).Thesearealso H2A HAT complex (Sykes et al., 2006; Tang et al., recurrent translocation partners with the MLL gene (Slany 2006), the homolog of NuA4. Tip60 and p53 mutants et al., 1998; Schreiner et al., 1999; Zeisig et al., 2004). AF-9 are sensitive to DNA damage (Legube et al., 2004), interacts with another human chromatin-modifying likewise YNG2 mutant phenotypes are suggestive of a

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5380 role in DNA damage response (Choy and Kron, 2002). genome-wide mapping of binding sites for chromatin- In contrast to Yng2’s role in promoting p53-dependent modifying enzymes. In concert with genome-wide maps transcription, Yng1 in NuA3 was observed to inhibit of chromatin modifications themselves, it has been p53 transcription. In both yng1D and sas3D mutants, possible to devise detailed interaction network models p53-dependent transcription is increased (Nourani et al., that integrate sites of action and transcriptional effects 2003). of many different chromatin modifiers. For example, A clear human homolog for the NuA4 component such an analysis has been performed for Esa1 (Robert Tra1 is TRAAP. TRA1 is essential for viability in yeast et al., 2004; Pokholok et al., 2005). This data set (Saleh et al., 1998), and its overexpression rescues provides insights into acetylation, deacetylation and mcm5/cdc46 mutants. MCM5 encodes a protein that methylation, and should prove useful in defining functions not only in DNA replication, but like Esa1, conserved human target genes and global effects on has a role in transcriptional silencing (Dziak et al., modification that may be especially relevant when 2003). Tra1 is also a component of the SAGA and SLIK thinking about nontranscription-based functions, such Gcn5-containing HAT complexes, similarly, TRAAP as DNA repair. is associated with PCAF and GCN5 HATs in -wide protein interaction maps that have cells (Grant et al., 1998; Pray-Grant et al., 2002; been developed through both affinity-tagging strategies Sterner et al., 2002). This conserved association with and two-hybrid assays provide additional resources for transcriptional activators (Vassilev et al., 1998) is thinking about uncharacterized human proteins with also exemplified by the ability of TRAAP to interact yeast homologs. Access to these data sets are readily with c-Myc and E2F-1 to promote their oncogenic available at the Saccharomyces Genome Database potential (McMahon et al., 1998; reviewed in Murr (http://www.yeastgenome.org), where simple gene-spe- et al., 2007). cific searches provide consolidated information with A less well-studied component of NuA3 is Nto1, links to primary sources. In combination with genome- which was only recently reported to be part of the wide mutant analyses (SGA and SLAM analyses, see complex (Taverna et al., 2006). Its precise function is not Tong et al., 2001; Ooi et al., 2006), powerful physical yet known, but it is similar to human Jade and BRPF and functional interaction maps in yeast now exist. proteins (Doyon et al., 2006). Human Jade is part of the From these studies, many additional MYST complex- HBO1 MYST HAT complex, whereas BRPF is a MOZ/ interacting proteins have been found. Although, they do MORF complex component. Jade itself has close not appear to be stable components of the biochemically connections to human cancer, as it is reported to purified complexes, they may prove to be important interact with the von Hippel–Lindau tumor suppressor regulatory or targeting factors. Because these additional as well as human Tip60 (Zhou et al., 2002; Panchenko MYST-implicated factors have conserved homologs, et al., 2004). they point to molecules that are worthy of closer Other yeast MYST complex components have clear examination in human cells and disease models. molecular homologs in humans (Table 1), but have not Where especially clear functional correlations are yet been extensively studied. However, their mutant possible, yeast may be a fruitful platform for small phenotypes and in some cases essential nature in yeast molecule and natural product screening for potential suggest potential for critical functions in humans, many pharmacological modulators of activity (Bedalov et al., of which have roles in cancer processes. It may be useful 2001; Grozinger et al., 2001; Olaharski et al., 2005), as to consider these under-studied homologs with high has proven of value in the sirtuin deacetylases. The priority as candidate disease genes or for knockdown sirtuin deacetylases and the MYST HATs are broadly studies. conserved chromatin modifiers that deserve increased attention as therapeutic targets. Although the primary focus on MYST protein Genomic and proteomic studies in yeast provide clues function has been acetylation, studies in yeast described for the future above are already pointing to clear functional relationships with other classes of modifiers, including deacetylases The completion of the S. cerevisiae genome as the first and methyltransferases. Understanding interactions and eukaryotic full-DNA sequence provided a platform for synergy of modifications will ultimately provide even more the pioneering development of large-scale genomic and refined approaches for understanding mechanisms of proteomic tools. These allowed analysis of individual disease and potential combinatorial therapeutics for genes, as well as evaluation of organismal effects of muta- their management. tions and physiological perturbations. As the human genome sequence was completed and its annotation becomes increasingly refined, much of the progress made Acknowledgements with yeast will be useful in directly informing us about We thank current and previous collaborators and lab members human gene functions and providing hypotheses for for their contributions to our work and M Krick and R Darst mechanisms of disease. for comments on this manuscript. Our laboratory has been Some of the notable successes and pioneering studies supported by the National Institutes of Health and the in yeast have been in the development of expression University of California Cancer Research Coordinating arrays that have subsequently been combined with Committee.

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5381 References

Akhtar A, Zink D, Becker PB. (2000). Chromodomains are Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee protein–RNA interaction modules. Nature 407: 405–409. KK et al. (2005). Histone H3 methylation by Set2 directs Allard S, Utley RT, Savard J, Clarke A, Grant P, Brandl CJ deacetylation of coding regions by Rpd3S to suppress et al. (1999). NuA4, an essential transcription adaptor/ spurious intragenic transcription. Cell 123: 581–592. histone H4 acetyltransferase complex containing Esa1p Choy JS, Kron SJ. (2002). NuA4 subunit Yng2 function in and the ATM-related cofactor Tra1p. EMBO J 18: intra-S-phase DNA damage response. Mol Cell Biol 22: 5108–5119. 8215–8225. Altaf M, Saksouk N, Coˆ te´ J. (2007). Histone modifications in Choy JS, Tobe BT, Huh JH, Kron SJ. (2001). Yng2p- response to DNA damage. Mutat Res 618: 81–90. dependent NuA4 histone H4 acetylation activity is required Anafi M, Yang YF, Barlev NA, Govindan MV, Berger SL, for mitotic and meiotic progression. J Biol Chem 276: Butt TR et al. (2000). GCN5 and ADA adaptor proteins 43653–43662. regulate triiodothyronine/GRIP1 and SRC-1 coactivator- Clarke AS, Lowell JE, Jacobson SJ, Pillus L. (1999). Esa1p is dependent gene activation by the human thyroid hormone an essential histone acetyltransferase required for cell cycle receptor. Mol Endocrinol 14: 718–732. progression. Mol Cell Biol 19: 2515–2526. Avvakumov N, Coˆ te´ J. (2007). The MYST family of histone Clarke AS, Samal E, Pillus L. (2006). Distinct roles for the acetyltransferases and their intimate links to cancer. essential MYST family HAT Esa1p in transcriptional Oncogene 26: 5395–5407. silencing. Mol Biol Cell 17: 1744–1757. Babiarz JE, Halley JE, Rine J. (2006). Telomeric hetero- Daniel JA, Pray-Grant MG, Grant PA. (2005). Effector chromatin boundaries require NuA4-dependent acetylation proteins for methylated histones: an expanding family. Cell of histone variant H2A.Z in Saccharomyces cerevisiae. Genes Cycle 4: 919–926. Dev 20: 700–710. Debernardi S, Bassini A, Jones LK, Chaplin T, Linder B, de Baker SP, Grant PA. (2007). The SAGA continues: expanding Bruijn DR et al. (2002). The MLL fusion partner AF10 the cellular role of a transcriptional co-activator complex. binds GAS41, a protein that interacts with the human SWI/ Oncogene 26: 5329–5340. SNF complex. Blood 99: 275–281. Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon Downs JA, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, JA. (2001). Identification of a small molecule inhibitor of Bouchard N et al. (2004). Binding of chromatin-modifying Sir2p. Proc Natl Acad Sci USA 98: 15113–15118. activities to phosphorylated histone H2A at DNA damage Bird AW, Yu DY, Pray-Grant MG, Qiu Q, Harmon KE, sites. Mol Cell 16: 979–990. Megee PC et al. (2002). Acetylation of histone H4 by Esa1 is Doyon Y, Cayrou C, Ullah M, Landry AJ, Coˆ te´ V, Selleck W required for DNA double-strand break repair. Nature 419: et al. (2006). ING tumor suppressor proteins are critical 411–415. regulators of chromatin acetylation required for genome Bittner CB, Zeisig DT, Zeisig BB, Slany RK. (2004). Direct expression and perpetuation. Mol Cell 21: 51–64. physical and functional interaction of the NuA4 complex Doyon Y, Selleck W, Lane WS, Tan S, Coˆ te´ J. (2004). components Yaf9p and Swc4p. Eukaryot Cell 3: 976–983. Structural and functional conservation of the NuA4 histone Borrow J, Shearman AM, Stanton Jr VP, Becher R, Collins T, acetyltransferase complex from yeast to humans. Mol Cell Williams AJ et al. (1996). The t(7;11)(p15;p15) translocation Biol 24: 1884–1896. in acute myeloid leukaemia fuses the genes for nucleoporin Dziak R, Leishman D, Radovic M, Tye BK, Yankulov K. NUP98and class I homeoprotein HOXA9. Nat Genet 12: (2003). Evidence for a role of MCM (mini-chromosome 159–167. maintenance)5 in transcriptional repression of sub-telomeric Boudreault AA, Cronier D, Selleck W, Lacoste N, Utley RT, and Ty-proximal genes in Saccharomyces cerevisiae. J Biol Allard S et al. (2003). Yeast enhancer of polycomb defines Chem 278: 27372–27381. global Esa1-dependent acetylation of chromatin. Genes Dev Ehrenhofer-Murray AE, Rivier DH, Rine J. (1997). The role 17: 1415–1428. of Sas2, an acetyltransferase homologue of Saccharomyces Brachmann RK, Vidal M, Boeke JD. (1996). Dominant- cerevisiae, in silencing and ORC function. Genetics 145: negative p53 mutations selected in yeast hit cancer hot spots. 923–934. Proc Natl Acad Sci USA 93: 4091–4095. Eisen A, Utley RT, Nourani A, Allard S, Schmidt P, Lane WS Brown CE, Howe L, Sousa K, Alley SC, Carrozza MJ, Tan S et al. (2001). The yeast NuA4 and Drosophila MSL et al. (2001). Recruitment of HAT complexes by direct complexes contain homologous subunits important for activator interactions with the ATM-related Tra1 subunit. transcription regulation. J Biol Chem 276: 3484–3491. Science 292: 2333–2337. Galarneau L, Nourani A, Boudreault AA, Zhang Y, Heliot L, Brown K, Chen Y, Underhill TM, Mymryk JS, Torchia J. Allard S et al. (2000). Multiple links between the NuA4 (2003). The coactivator p/CIP/SRC-3 facilitates retinoic acid histone acetyltransferase complex and epigenetic control receptor signaling via recruitment of GCN5. J Biol Chem of transcription. Mol Cell 5: 927–937. 278: 39402–39412. Georgiakaki M, Chabbert-Buffet N, Dasen B, Meduri G, Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson Wenk S, Rajhi L et al. (2006). Ligand-controlled interaction DG, Roth SY et al. (1996). Tetrahymena histone acetyl- of histone acetyltransferase binding to ORC-1 (HBO1) with transferase A: a homolog to yeast Gcn5p linking histone the N-terminal transactivating domain of progesterone acetylation to gene activation. Cell 84: 843–851. receptor induces steroid receptor coactivator 1-dependent Burke TW, Cook JG, Asano M, Nevins JR. (2001). Replica- coactivation of transcription. Mol Endocrinol 20: 2122–2140. tion factors MCM2 and ORC1 interact with the histone Go´ mez EB, Espinosa JM, Forsburg SL. (2005). Schizosacchar- acetyltransferase HBO1. J Biol Chem 276: 15397–15408. omyces pombe mst2+ encodes a MYST family histone Cairns BR, Henry NL, Kornberg RD. (1996). TFG/TAF30/ acetyltransferase that negatively regulates telomere silen- ANC1, a component of the yeast SWI/SNF complex that cing. Mol Cell Biol 25: 8887–8903. is similar to the leukemogenic proteins ENL and AF-9. Grant PA, Schieltz D, Pray-Grant MG, Yates III JR, Mol Cell Biol 16: 3308–3316. Workman JL. (1998). The ATM-related cofactor Tra1 is

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5382 a component of the purified SAGA complex. Mol Cell 2: Kobor MS, Venkatasubrahmanyam S, Meneghini MD, Gin 863–867. JW, Jennings JL, Link AJ et al. (2004). A protein complex Grozinger CM, Chao ED, Blackwell HE, Moazed D, containing the conserved Swi2/Snf2-related ATPase Swr1p Schreiber SL. (2001). Identification of a class of small deposits histone variant H2A.Z into euchromatin. PLoS molecule inhibitors of the sirtuin family of NAD-dependent Biol 2: E131. deacetylases by phenotypic screening. J Biol Chem 276: Krogan NJ, Baetz K, Keogh MC, Datta N, Sawa C, Kwok TC 38837–38843. et al. (2004). Regulation of chromosome stability by the Grunstein M. (1990). Histone function in transcription. Annu histone H2A variant Htz1, the Swr1 chromatin remodeling Rev Cell Biol 6: 643–678. complex, and the histone acetyltransferase NuA4. Proc Natl Gupta A, Sharma GG, Young CS, Agarwal M, Smith ER, Acad Sci USA 101: 13513–13518. Paull TT et al. (2005). Involvement of human MOF in ATM Krogan NJ, Cagney G, Yu H, Zhong G, Guo X, Ignatchenko function. Mol Cell Biol 25: 5292–5305. A et al. (2006). Global landscape of protein complexes Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi JC. (1997). in the yeast Saccharomyces cerevisiae. Nature 440: mof, A putative acetyl transferase gene related to the Tip60 637–643. and MOZ human genes and to the SAS genes of yeast, is Krogan NJ, Keogh MC, Datta N, Sawa C, Ryan OW, Ding H required for dosage compensation in Drosophila. EMBO J et al. (2003). A Snf2 family ATPase complex required for 16: 2054–2060. recruitment of the histone H2A variant Htz1. Mol Cell 12: Howe L, Auston D, Grant P, John S, Cook RG, Workman JL 1565–1576. et al. (2001). Histone H3 specific acetyltransferases are Le Masson I, Yu DY, Jensen K, Chevalier A, Courbeyrette R, essential for cell cycle progression. Genes Dev 15: 3144–3154. Boulard Y et al. (2003). Yaf9, a novel NuA4 histone acetyl- Howe L, Kusch T, Muster N, Chaterji R, Yates III JR, transferase subunit, is required for the cellular response to Workman JL. (2002). Yng1p modulates the activity of Sas3p spindle stress in yeast. Mol Cell Biol 23: 6086–6102. as a component of the yeast NuA3 histone acetyltransferase Legube G, Linares LK, Tyteca S, Caron C, Scheffner M, complex. Mol Cell Biol 22: 5047–5053. Chevillard-Briet M et al. (2004). Role of the histone acetyl Iizuka M, Matsui T, Takisawa H, Smith MM. (2006). transferase Tip60 in the p53 pathway. J Biol Chem 279: Regulation of replication licensing by acetyltransferase 44825–44833. Hbo1. Mol Cell Biol 26: 1098–1108. Li YC, Cheng TH, Gartenberg MR. (2001). Establishment of Iizuka M, Stillman B. (1999). Histone acetyltransferase HBO1 transcriptional silencing in the absence of DNA replication. interacts with the ORC1 subunit of the human initiator Science 291: 650–653. protein. J Biol Chem 274: 23027–23034. Liu Y, Vidanes G, Lin YC, Mori S, Siede W. (2000). Jacobson S, Pillus L. (2004). Molecular requirements for gene Characterization of a Saccharomyces cerevisiae homologue expression mediated by targeted histone acetyltransferases. of Schizosaccharomyces pombe Chk1 involved in DNA- Mol Cell Biol 24: 6029–6039. damage-induced M-phase arrest. Mol Gen Genet 262: John S, Howe L, Tafrov ST, Grant PA, Sternglanz R, 1132–1146. Workman JL. (2000). The something about silencing Lonard DM, O’Malley BW. (2006). The expanding cosmos of protein, Sas3, is the catalytic subunit of NuA3, a yTA- nuclear receptor coactivators. Cell 125: 411–414. F(II)30-containing HAT complex that interacts with the Martin DG, Grimes DE, Baetz K, Howe L. (2006). Methyla- Spt16 subunit of the yeast CP (Cdc68/Pob3)-FACT com- tion of histone H3 mediates the association of the NuA3 plex. Genes Dev 14: 1196–1208. histone acetyltransferase with chromatin. Mol Cell Biol 26: Kabani M, Michot K, Boschiero C, Werner M. (2005). Anc1 3018–3028. interacts with the catalytic subunits of the general transcrip- McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, tion factors TFIID and TFIIF, the chromatin remodeling Cole MD. (1998). The novel ATM-related protein TRRAP complexes RSC and INO80, and the histone acetyltransfer- is an essential cofactor for the c-Myc and E2F oncoproteins. ase complex NuA3. Biochem Biophys Res Commun 332: Cell 94: 363–374. 398–403. Meijsing SH, Ehrenhofer-Murray AE. (2001). The silencing Kamine J, Elangovan B, Subramanian T, Coleman D, complex SAS-I links histone acetylation to the assembly of Chinnadurai G. (1996). Identification of a cellular repressed chromatin by CAF-I and Asf1 in Saccharomyces protein that specifically interacts with the essential cysteine cerevisiae. Genes Dev 15: 3169–3182. region of the HIV-1 Tat transactivator. Virology 216: Millar CB, Xu F, Zhang K, Grunstein M. (2006). Acetylation 357–366. of H2AZ Lys 14 is associated with genome-wide gene Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, activity in yeast. Genes Dev 20: 711–722. Collins SR et al. (2005). Cotranscriptional Set2 methylation Murr R, Vaissie` re T, Sawan C, Shukla V, Herceg Z. (2007). of histone H3 lysine 36 recruits a repressive Rpd3 complex. Orchestration of chromatin-based processes: mind the Cell 123: 593–605. TRRAP. Oncogene 26: 5358–5372. Keogh MC, Mennella TA, Sawa C, Berthelet S, Krogan NJ, Nishikawa J, Saito K, Goto J, Dakeyama F, Matsuo M, Wolek A et al. (2006). The Saccharomyces cerevisiae histone Nishihara T. (1999). New screening methods for chemicals H2A variant Htz1 is acetylated by NuA4. Genes Dev 20: with hormonal activities using interaction of nuclear 660–665. hormone receptor with coactivator. Toxicol Appl Pharmacol Kimura A, Umehara T, Horikoshi M. (2002). Chromosomal 154: 76–83. gradient of histone acetylation established by Sas2p and Nourani A, Doyon Y, Utley RT, Allard S, Lane WS, Coˆ te´ J. Sir2p functions as a shield against gene silencing. Nat Genet (2001). Role of an ING1 growth regulator in transcriptional 32: 370–377. activation and targeted histone acetylation by the NuA4 Kirchmaier AL, Rine J. (2001). DNA replication-independent complex. Mol Cell Biol 21: 7629–7640. silencing in S. cerevisiae. Science 291: 646–650. Nourani A, Howe L, Pray-Grant MG, Workman JL, Grant Kleff S, Andrulis ED, Anderson CW, Sternglanz R. (1995). PA, Coˆ te´ J. (2003). Opposite role of yeast ING family Identification of a gene encoding a yeast histone H4 members in p53-dependent transcriptional activation. J Biol acetyltransferase. J Biol Chem 270: 24674–24677. Chem 278: 19171–19175.

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5383 Nourani A, Utley RT, Allard S, Coˆ te´ J. (2004). Recruitment of Shia WJ, Li B, Workman JL. (2006). SAS-mediated acetyl- the NuA4 complex poises the PHO5 promoter for chroma- ation of histone H4 Lys 16 is required for H2A.Z incorpor- tin remodeling and activation. EMBO J 23: 2597–2607. ation at subtelomeric regions in Saccharomyces cerevisiae. Ogryzko VV. (2001). Mammalian histone acetyltransferases Genes Dev 20: 2507–2512. and their complexes. Cell Mol Life Sci 58: 683–692. Shia WJ, Osada S, Florens L, Swanson SK, Washburn MP, Olaharski AJ, Rine J, Marshall BL, Babiarz J, Zhang L, Workman JL. (2005). Characterization of the yeast Verdin E et al. (2005). The flavoring agent dihydrocoumarin trimeric–SAS acetyltransferase complex. J Biol Chem 280: reverses epigenetic silencing and inhibits sirtuin deacetylases. 11987–11994. PLoS Genet 1: e77. Slany RK, Lavau C, Cleary ML. (1998). The oncogenic Ooi SL, Pan X, Peyser BD, Ye P, Meluh PB, Yuan DS et al. capacity of HRX-ENL requires the transcriptional transac- (2006). Global synthetic-lethality analysis and yeast func- tivation activity of ENL and the DNA binding motifs of tional profiling. Trends Genet 22: 56–63. HRX. Mol Cell Biol 18: 122–129. Osada S, Sutton A, Muster N, Brown CE, Yates III JR, Smith ER, Eisen A, Gu W, Sattah M, Pannuti A, Zhou J et al. Sternglanz R et al. (2001). The yeast SAS (something about (1998a). ESA1 is a histone acetyltransferase that is essential silencing) protein complex contains a MYST-type putative for growth in yeast. Proc Natl Acad Sci USA 95: 3561–3565. acetyltransferase and functions with chromatin assembly Smith ER, Pannuti A, Gu W, Steurnagel A, Cook RG, Allis CD factor ASF1. Genes Dev 15: 3155–3168. et al. (2000). The Drosophila MSL complex acetylates histone Panchenko MV, Zhou MI, Cohen HT. (2004). von Hippel– H4 at lysine 16, a chromatin modification linked to dosage Lindau partner Jade-1 is a transcriptional co-activator associ- compensation. MolCellBiol20: 312–318. ated with histone acetyltransferase activity. JBiolChem279: Smith JS, Brachmann CB, Pillus L, Boeke JD. (1998b). 56032–56041. Distribution of a limited Sir2 protein pool regulates the Parthun MR, Widom J, Gottschling DE. (1996). The major strength of yeast rDNA silencing and is modulated by Sir4p. cytoplasmic histone acetyltransferase in yeast: links to Genetics 149: 1205–1219. chromatin replication and histone metabolism. Cell 87: Sterner DE, Belotserkovskaya R, Berger SL. (2002). SALSA, 85–94. a variant of yeast SAGA, contains truncated Spt7, which Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, correlates with activated transcription. Proc Natl Acad Sci Lee TI et al. (2005). Genome-wide map of nucleo- USA 99: 11622–11627. some acetylation and methylation in yeast. Cell 122: Sterner DE, Berger SL. (2000). Acetylation of histones and 517–527. transcription-related factors. Microbiol Mol Biol Rev 64: Pray-Grant MG, Schieltz D, McMahon SJ, Wood JM, 435–459. Kennedy EL, Cook RG et al. (2002). The novel Suka N, Luo K, Grunstein M. (2002). Sir2p and Sas2p SLIK histone acetyltransferase complex functions in opposingly regulate acetylation of yeast histone H4 the yeast retrograde response pathway. Mol Cell Biol 22: lysine16 and spreading of heterochromatin. Nat Genet 32: 8774–8786. 378–383. Rea S, Xouri G, Akhtar A. (2007). Males absent on the first Suka N, Suka Y, Carmen AA, Wu J, Grunstein M. (2001). (MOF): from flies to humans. Oncogene 26: 5385–5394. Highly specific antibodies determine histone acetylation site Reid JL, Iyer VR, Brown PO, Struhl K. (2000). Coordinate usage in yeast heterochromatin and euchromatin. Mol Cell regulation of yeast ribosomal protein genes is associated 8: 473–479. with targeted recruitment of Esa1 histone acetylase. Mol Sutton A, Shia WJ, Band D, Kaufman PD, Osada S, Cell 6: 1297–1307. Workman JL et al. (2003). Sas4 and Sas5 are required for Reifsnyder C, Lowell J, Clarke A, Pillus L. (1996). Yeast SAS the histone acetyltransferase activity of Sas2 in the SAS silencing genes and human genes associated with AML and complex. J Biol Chem 278: 16887–16892. HIV-1 Tat interactions are homologous with acetyltrans- Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, ferases. Nat Genet 14: 42–49. Lane WS et al. (2006). Acetylation of the p53 DNA-binding Robert F, Pokholok DK, Hannett NM, Rinaldi NJ, Chandy domain regulates apoptosis induction. Mol Cell 24: 841–851. M, Rolfe A et al. (2004). Global position and recruitment Takechi S, Nakayama T. (1999). Sas3 is a histone acetyl- of HATs and HDACs in the yeast genome. Mol Cell 16: transferase and requires a zinc finger motif. Biochem Biophys 199–209. Res Commun 266: 405–410. Saleh A, Schieltz D, Ting N, McMahon SB, Litchfield DW, Tamburini BA, Tyler JK. (2005). Localized histone acetylation Yates III JR et al. (1998). Tra1p is a component of the yeast and deacetylation triggered by the homologous recombina- Ada. Spt transcriptional regulatory complexes. J Biol Chem tion pathway of double-strand DNA repair. Mol Cell Biol 273: 26559–26565. 25: 4903–4913. Schreiner SA, Garcia-Cuellar MP, Fey GH, Slany RK. Tang Y, Luo J, Zhang W, Gu W. (2006). Tip60-dependent (1999). The leukemogenic fusion of MLL with ENL creates acetylation of p53 modulates the decision between cell–cycle a novel transcriptional transactivator. Leukemia 13: arrest and apoptosis. Mol Cell 24: 827–839. 1525–1533. Taverna SD, Ilin S, Rogers RS, Tanny JC, Lavender H, Li H Selleck W, Fortin I, Sermwittayawong D, Coˆ te´ J, Tan S. et al. (2006). Yng1 PHD finger binding to H3 trimethylated (2005). The Saccharomyces cerevisiae Piccolo NuA4 histone at K4 promotes NuA3 HAT activity at K14 of H3 and acetyltransferase complex requires the Enhancer of Poly- transcription at a subset of targeted ORFs. Mol Cell 24: comb A domain and chromodomain to acetylate nucleo- 785–796. somes. Mol Cell Biol 25: 5535–5542. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Sharma M, Zarnegar M, Li X, Lim B, Sun Z. (2000). (2001). Histone acetylation and disease. Cell Mol Life Sci Androgen receptor interacts with a novel MYST protein, 58: 728–736. HBO1. J Biol Chem 275: 35200–35208. Tong AH, Evangelista M, Parsons AB, Xu H, Bader GD, Shen X, Xiao H, Ranallo R, Wu WH, Wu C. (2003). Page N et al. (2001). Systematic genetic analysis with Modulation of ATP-dependent chromatin-remodeling com- ordered arrays of yeast deletion mutants. Science 294: plexes by inositol polyphosphates. Science 299: 112–114. 2364–2368.

Oncogene Yeast MYST HATs and human cancer A Lafon et al 5384 Troke PJ, Kindle KB, Collins HM, Heery DM. (2006). MOZ Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin fusion proteins in acute myeloid leukaemia. Biochem Soc ME, Fuchs U et al. (2004). Hoxa9 and Meis1 are key targets Symp 73: 23–39. for MLL-ENL-mediated cellular immortalization. Mol Cell Utley RT, Coˆ te´ J. (2003). The MYST family of histone acetyl- Biol 24: 617–628. transferases. Curr Top Microbiol Immunol 274: 203–236. Zhang H, Richardson DO, Roberts DN, Utley R, Erdjument- Vassilev A, Yamauchi J, Kotani T, Prives C, Avantaggiati Bromage H, Tempst P et al. (2004). The Yaf9 component of ML, Qin J et al. (1998). The 400 kDa subunit of the PCAF the SWR1 and NuA4 complexes is required for proper gene histone acetylase complex belongs to the ATM superfamily. expression, histone H4 acetylation, and Htz1 replacement Mol Cell 2: 869–875. near telomeres. Mol Cell Biol 24: 9424–9436. Vogelauer M, Wu J, Suka N, Grunstein M. (2000). Global Zhang W, Xia X, Reisenauer MR, Hemenway CS, Kone BC. histone acetylation and deacetylation in yeast. Nature 408: (2006). Dot1a-AF9 complex mediates histone H3 495–498. Lys-79 hypermethylation and repression of ENaCalpha Xu EY, Kim S, Replogle K, Rine J, Rivier DH. (1999a). in an aldosterone-sensitive manner. J Biol Chem 281: Identification of SAS4 and SAS5, two genes that regulate 18059–18068. silencing in Saccharomyces cerevisiae. Genetics 153: 13–23. Zhang Y, Rowley JD. (2006). Chromatin structural elements Xu EY, Kim S, Rivier DH. (1999b). SAS4 and SAS5 are and chromosomal translocations in leukemia. DNA Repair -specific regulators of silencing in Saccharomyces (Amst) 5: 1282–1297. cerevisiae. Genetics 153: 25–33. Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT. Yan Y, Barlev NA, Haley RH, Berger SL, Marmorstein R. (2002). The von Hippel–Lindau tumor suppressor stabilizes (2000). Crystal structure of yeast Esa1 suggests a unified novel plant homeodomain protein Jade-1. J Biol Chem 277: mechanism for catalysis and substrate binding by histone 39887–39898. acetyltransferases. Mol Cell 6: 1195–1205. Zong H, Li Z, Liu L, Hong Y, Yun X, Jiang J et al. (2005). Yang XJ. (2004). The diverse superfamily of lysine acetyl- Cyclin-dependent kinase 11(p58) interacts with HBO1 and transferases and their roles in leukemia and other diseases. enhances its histone acetyltransferase activity. FEBS Lett Nucleic Acids Res 32: 959–976. 579: 3579–3588.

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