males absent on the first: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | References

Gene name - males absent on the first

Synonyms -

Cytological map position - 5C2-4

Function - histone acetyltransferase

Keywords - dosage compensation

Symbol - mof

FlyBase ID: FBgn0014340

Genetic map position - 1-13.8

Classification - SAS/MOZ family, C2HC type zinc finger

Cellular location - nuclear



NCBI links: Precomputed BLAST | Entrez Gene
Recent literature
Pushpavalli, S. N., Sarkar, A., Ramaiah, M. J., Koteswara Rao, G., Bag, I., Bhadra, U. and Pal-Bhadra, M. (2015). Drosophila MOF regulates DIAP1 and induces apoptosis in a JNK dependent pathway. Apoptosis [Epub ahead of print]. PubMed ID: 26711898
Summary:
Histone modulations have been implicated in various cellular and developmental processes where in Drosophila Mof is involved in acetylation of H4K16. Reduction in the size of larval imaginal discs is observed in the null mutants of mof with increased apoptosis. Deficiency involving Hid, Reaper and Grim [H99] alleviated mof RNAi induced apoptosis in the eye discs. mof RNAi induced apoptosis leads to activation of caspases which is suppressed by over expression of caspase inhibitors like P35 and Diap1 clearly depicting the role of caspases in programmed cell death. Also apoptosis induced by knockdown of mof is rescued by JNK mutants of bsk and tak1 indicating the role of JNK in mof RNAi induced apoptosis. The adult eye ablation phenotype produced by ectopic expression of Hid, Rpr and Grim, was restored by over expression of Mof. Accumulation of Mof at the Diap1 promoter 800 bp upstream of the transcription start site in wild type larvae is significantly higher (up to twofolds) compared to mof mutants. This enrichment coincides with modification of histone H4K16Ac indicating an induction of direct transcriptional up regulation of Diap1 by Mof. Based on these results it is proposed that apoptosis triggered by mof RNAi proceeds through a caspase-dependent and JNK mediated pathway.
Schunter, S., Villa, R., Flynn, V., Heidelberger, J. B., Classen, A. K., Beli, P. and Becker, P. B. (2017). Ubiquitylation of the acetyltransferase MOF in Drosophila melanogaster. PLoS One 12(5): e0177408. PubMed ID: 28510597
Summary:
The nuclear acetyltransferase MOF (KAT8 in mammals) is a subunit of at least two multi-component complexes involved in transcription regulation. In the context of complexes of the 'Non-Specific-Lethal' (NSL) type it controls transcription initiation of many nuclear housekeeping genes and of mitochondrial genes. While this function is conserved in metazoans, MOF has an additional, specific function in Drosophila in the context of dosage compensation. As a subunit of the male-specific-lethal dosage compensation complex (MSL-DCC) it contributes to the doubling of transcription output from the single male X chromosome by acetylating histone H4. Proper dosage compensation requires finely tuned levels of MSL-DCC and an appropriate distribution of MOF between the regulatory complexes. The amounts of DCC formed depends directly on the levels of the male-specific MSL2, which orchestrates the assembly of the DCC, including MOF recruitment. Earlier studies found that MSL2 is an E3 ligase that ubiquitylates most MSL proteins, including MOF, suggesting that ubiquitylation may contribute to a quality control of MOF's overall levels and folding state as well as its partitioning between the complex entities. This study used mass spectrometry to map the lysines in MOF that are ubiquitylated by MSL2 in vitro and identified in vivo ubiquitylation sites of MOF in male and female cells. MSL2-specific ubiquitylation in vivo could not be traced due to the dominance of other, sex-independent ubiquitylation events and conceivably may be rare or transient. Expressing appropriately mutated MOF derivatives, the importance of the ubiquitylated lysines for dosage compensation was assessed by monitoring DCC formation and X chromosome targeting in cultured cells, and by genetic complementation of the male-specific-lethal mof2 allele in flies. This study provides a comprehensive analysis of MOF ubiquitylation as a reference for future studies.
Lee, H., Cho, D. Y., Wojtowicz, D., Harbison, S. T., Russell, S., Oliver, B. and Przytycka, T. (2017). Dosage-dependent expression variation suppressed on the Drosophila male X chromosome. G3 (Bethesda) [Epub ahead of print]. PubMed ID: 29242386
Summary:
DNA copy number variation is associated with many high phenotypic heterogeneity disorders. This study systematically examined the impact of Drosophila deletions on gene expression profiles to ask if increased expression variability due to reduced gene dose might underlie this phenotypic heterogeneity. Indeed, one dose genes were found to have higher gene expression variability relative to two dose genes. Interestingly, expression variability was related to the magnitude of expression compensation, suggesting that gene dose reduction induced regulation is noisy. In a remarkable exception to this rule the single X chromosome of males showed reduced expression variability, even compared to two dose genes. Analysis of sex transformed flies indicates that X expression variability is independent of the male differentiation program. Instead, a correlation was uncovered between occupancy of the chromatin modifying protein encoded by males absent on first (mof) and expression variability, linking noise suppression to the specialized X chromosome dosage compensation system. MOF occupancy on autosomes in both sexes lowered transcriptional noise as well. The results demonstrate that gene deletions can lead to heterogeneous responses, which are often noisy. This has implications for understanding gene network regulatory interactions and phenotypic heterogeneity. Additionally, chromatin modification appears to play a role in dampening transcriptional noise.
BIOLOGICAL OVERVIEW

Dosage compensation is a regulatory process that ensures that males and females have equal amounts of X-chromosome gene products. In Drosophila, this is achieved by a 2-fold enhancement of X-linked gene transcription in males, relative to females. The enhancement of transcription is mediated by the activity of a group of regulatory genes whose protein products form a complex that is preferentially associated with numerous sites on the X chromosome in somatic cells of males but not of females. These regulatory genes are referred to as male-specific lethals because of the male-specific lethality of their loss-of-function alleles. Binding of the dosage compensation complex is correlated with a significant increase in the presence of a specific histone isoform, histone 4 acetylated at Lys16, on this chromosome. The phenotype of male-specific lethality was used to screen the X chromosome of Drosophila melanogaster for ethyl methane sulfonate (EMS)-induced mutations, thereby identifying additional genes that might be involved in the regulatory process of dosage compensation. In one such mutation. males-absent on the first (mof), dying mutant males lack the X-associated isoform of H4Ac16. Mof exhibits the signature motif for the acetyl coenzyme A binding site found in numerous and diverse acetyl transferases. Mof is a histone acetyl transferase (HAT) responsible for the particular histone acetylation involved in the male-specific hypertranscription of X-linked genes (Hilfiker, 1997).

Mutant mof males can develop to the third larval instar or the prepupal stage but fail to metamorphose and to hatch; the viability of mutant females is unaffected. Two lines of evidence establish that this male-specific lethality is due to a defect in dosage compensation. The first involves the effect of the mof mutation on the binding of the other dosage compensation regulatory factors to the X chromosome, as well as the effect of this mutation on the normal consequences that this binding has on nucleosomal structure. The association of Msl-1 and Msl-2 with the X chromosome of mutant mof male larvae is somewhat reduced, while that of Mle is substantially reduced. The X-specific isoform of histone 4 (H4Ac16) appears to be absent. The apparent reduction in the level of Msl-1 and Msl-2 bound to the X chromosome may be the indirect result of the poor cytological condition of the salivary glands of moribund mutant male larvae. In contrast, the effect of the mutation on the level of Mle appears significant. Msl-1 and Msl-2 fail to associate with the X chromosome in male larvae homozygous for loss-of-function mle mutations. Yet, RNase treatment of the male X chromosome removes Mle while leaving Msl-1 and Msl-2 undisturbed. In light of these considerations it may appear that, while Mle is necessary for the initial binding of the dosage compensation complex to the X chromosome in normal males, its association with this chromosome may be stabilized through an interaction with nascent transcripts or with an unidentified RNA component of chromatin. By interfering with the presence of H4Ac16 on the X chromosome and with hypertranscription, the mof mutation may destabilize this interaction (Hilfiker, 1997).

The second line of evidence demonstrating that mof has a functional role in dosage compensation derives from the ability of the mof mutation to prevent the lethality caused by the ectopic expression of a particular dosage compensation regulatory factor in females. Females that carry a transduced msl-2 gene under the control of a heat shock promoter exhibit a very long developmental delay and a significant loss of viability. This is caused by the fact that the presence of Msl-2 is sufficient for the formation of the dosage compensation complex and its association with both X chromosomes, presumably leading to an abnormally high level of X-linked gene products. Normal development is restored in these females by the presence in their genome of mle or msl-3 null alleles in homozygous condition or by the presence of one Msl-1 loss-of-function allele, i.e. of a single dose of the wild-type Msl-1 gene. The same level of rescue is achieved by replacing one wild-type copy of mof with either a deficiency for the locus (L. Rastelli and M. Kuroda, personal communication to Hilfiker, 1997) or with the mof mutation (Hilfiker, 1997).

The presence of Mof homologs in organisms as divergent as yeast and humans suggests that these proteins play an important cellular role, presumably in the modulation of transcription. Such a role, documented with respect to Mof homologs Tip60, SAS2 and SAS3, is strongly indicated with respect to Mof by its involvement in dosage compensation. In Drosophila, because the mof mutation is not lethal in females, the general transcriptional function of the ancestral Mof protein appears to have been appropriated by the dosage compensation mechanism (which is male-specific) and to have been replaced in both males and females by the function of some other factor. The presence of the mof transcript in females, in which the Mof product is dispensable, is not an uncommon occurrence in Drosophila dosage compensation and, therefore, should not be interpreted as evidence of Mof function in this sex (Hilfiker, 1997).

In Drosophila, the hypertranscription of the X chromosome in males appears to be directly correlated with the presence of a particular isoform of histone 4, H4Ac16, that is absent or significantly less abundant on the X chromosomes of females, and on the autosomes of both sexes. This feature of the male X-chromosome chromatin appears to be conserved throughout the genus (Bone, 1996; Steinemann, 1996). In D.melanogaster, the presence of H4Ac16 has been shown to result from the binding to the X chromosome of the complex responsible for the mechanism of dosage compensation (Hilfiker, 1994). The specific function of MOF in this regulatory mechanism is indicated by the presence of an apparent acetyl coenzyme A binding site. The functionality of this site is validated by the observation that replacement of Gly104 by an aspartate residue in the human spermidine/spermine acetyl transferase results in a protein with no measurable activity (Lu, 1996). Significantly, the glycine in question corresponds to Gly691 in MOF that, when replaced by a glutamic acid, leads to the absence of demonstrable H4Ac16 histone isoform on the X chromosome and to the male-lethal phenotype. These considerations have lead to the conclusion that MOF may be directly involved in the acetylation of histone 4 at Lys16 on the X chromosome of Drosophila males. MOF provides a functional link between this known nucleosomal modification and the transcriptional enhancement that is the basis of dosage compensation (Hilfiker, 1997).

Activation of transcription through histone H4 acetylation by Mof, an acetyltransferase essential for dosage compensation in Drosophila

While the link between acetylation of histone H4 at lysine 16 and the dosage compensated male X chromosome points to an involvement of the modification early on, a causal relationship between the two phenomena has been difficult to established. It has been considered possible that the same principle that promotes an increase in accessibility of genes on the male X chromosome to the transcription machinery may also increase the availability of the nucleosome substrate to a ubiquitous acetyltransferase. In this scenario, H4 acetylation would not be causal to the increased expression of X-linked genes in males, but both phenomena would profit from a common, yet unidentified cause. It has now been shown that acetylation of nucleosomes at H4 lysine 16 can lead to a remarkable relief of nucleosomal repression (Akhtar, 2000). Mof has been demonstrate to act is a histone acetyltransferase that acetylates chromatin specifically at histone H4 lysine 16. This acetylation relieves chromatin-mediated repression of transcription in vitro and in vivo if Mof is targeted to a promoter by fusion to a DNA-binding domain. Acetylation of chromatin by MOF, therefore, appears to be causally involved in transcriptional activation during dosage compensation. Dosage compensation in Drosophila therefore presents a strong case for a direct role of H4 acetylation on gene transcription in vivo (Akhtar, 2000).

Although required for dosage compensation in male flies, Mof is expressed in female cells to a similar extent as in males. While this observation raises the interesting issue of whether Mof has unknown functions in flies besides dosage compensation, it also highlights the importance of targeting of Mof specifically to the X chromosome in males. All histone acetyltransferases studied to date reside in large multiprotein complexes in cells. It is assumed that the histone acetyl transferase-associated subunits are involved in the targeting of HAT activity to specific sites of action, notably promoters. Targeting may involve direct interaction with promoter-bound transcription factors as has been shown for yeast ESA1. ESA1 resides in the large NuA4 complex for which an interaction with acidic activators, leading to targeted acetylation of histones, has been shown (Ikeda, 1999). Likewise, Mof is part of a multiprotein complex consisting of the known Msl proteins (Copps, 1998). In the case of dosage compensation that involves decondensation of an entire chromosome (a scenario whereby a key acetyltransferase is targeted to all promoters via factor interactions) appears less likely. Rather, the recent identification of high-affinity nucleation sites from which the dosage compensation complex may spread into the adjacent chromatin (Kelley, 1999) points to a targeting via X chromosome-specific sequence elements. Using indirect immunofluorescence on flies with varying mutant backgrounds, Lucchesi and colleagues (Gu, 1998) recently established a model for the assembly of the dosage compensation complex. According to their model, MSL1 and MSL2 first interact with chromatin in a site-specific manner. Recruitment of MOF to the complex requires prior interaction of the MLE protein (Gu, 1998). A possible scenario may be constructed in analogy to current models of long distance chromatin repression by the polycomb group (PcG) of proteins. It has been hypothesized that the PcG complex is initially targeted to dedicated polycomb response elements (PREs) and that a repressive chromatin structure spreads from there into the neighboring chromatin. The polycomb protein has recently been shown to directly contact nucleosomes via its C-terminal repression domain. It remains to be seen whether the observed interaction of Mof with nucleosomes solely reflects the substrate recognition, that is the interaction of the catalytic site with the histone H4 N-terminal tail, or whether second sites on the nucleosome or Mof are involved. Besides the HAT domain, a domain with similarity to the chromodomain, as well as a zinc finger of the Cys2-His-Cys type, has been noted in Mof (Akhtar, 2000 and references therein).

Hyperacetylation of histone H4 can lead to an increased access of transcription factors to nucleosomal DNA, to an unfolding of the nucleosomal fiber, and to activation of transcription on chromatin templates. However, hyperacetylation is an experimentally induced condition in cells that is not observed under physiological conditons. Histones are mainly monoacetylated in vivo, and the determinant of functional states appears to reside in the site specificity of acetylation rather than the extent of the modification. This has been nicely illustrated by the visualization of histone H4 on Drosophila polytene chromosomes: acetylation of H4 at lysine 16 paints the hyperactive X chromosome, while acetylation at lysine 12 is a hallmark of inactive heterochromatin. Site-specific acetylation may conceivably affect interactions of the histone H4 N terminus with either vicinal nucleosomes or nonhistone proteins. It is likely that these interactions may lead to alterations of the folding of the nucleosomal fiber and degree of chromatin compaction. Interactions of the H4 N-terminal amino acids K16-N25 with the H2A/H2B heterodimer occur in the nucleosome crystal, but it is unclear yet whether these would contribute to the folding of a physiological chromatin fiber. The quest for interacting factors with potential to discriminate between particular histone isoforms is ongoing, with no results reported to date (Akhtar, 2000 and references therein).

While it is clear that acetylation of H4 at lysine 16 suffices to increase transcription of model genes in vitro and in vivo, the mechanism is obscure by which it coordinately affects all genes on the male X chromosome. A change in higher order chromatin folding may affect the assembly of the basal transcription machinery in general or a step subsequent to initiation, such as the elongation rate. However, in vitro transcription reactions are not designed to monitor transcription elongation through nucleosomal arrays but rather to detect short transcripts. Furthermore, the ability of Mof to activate transcription in yeast when tethered to a promoter via a DNA-binding domain suggests that a rather local acetylation may lead to a significant stimulation of transcription. In vitro, recombinant MOF is able to boost transcription far more than just the 2-fold effect that it has in vivo. A precise doubling of X-derived RNA levels in males may hence either involve a feed-back mechanism or additional regulation at a posttranscriptional level, such as RNA stabilization (Akhtar, 2000).

Sex-specific phenotypes of histone H4 point mutants establish dosage compensation as the critical function of H4K16 acetylation in Drosophila

Acetylation of histone H4 at lysine 16 (H4K16) modulates nucleosome-nucleosome interactions and directly affects nucleosome binding by certain proteins. In Drosophila, H4K16 acetylation by the dosage compensation complex subunit Mof is linked to increased transcription of genes on the single X chromosome in males. This study analyzed Drosophila containing different H4K16 mutations or lacking Mof protein. An H4K16A mutation causes embryonic lethality in both sexes, whereas an H4K16R mutation permits females to develop into adults but causes lethality in males. The acetyl-mimic mutation H4K16Q permits both females and males to develop into adults. Complementary analyses reveal that males lacking maternally deposited and zygotically expressed Mof protein arrest development during gastrulation, whereas females of the same genotype develop into adults. Together, this demonstrates the causative role of H4K16 acetylation by Mof for dosage compensation in Drosophila and uncovers a previously unrecognized requirement for this process already during the onset of zygotic gene transcription (Copur, 2018).

Mutational analyses of histone amino acid residues that are subject to posttranslational modifications provide a direct approach for probing the physiological role of these residues and their modification. This study investigated the function of H4K16 and its acetylation in Drosophila by generating animals in which all nucleosomes in their chromatin were altered to constitutively carry a positively charged H4R16, an acetyl-mimic H4Q16, or a short apolar H4A16 substitution. These three types of chromatin changes have different physiological consequences that lead to the following main conclusions. First, H4R16 and H4Q16 chromatin both support development of female zygotes into adults. This suggests that, in females, modulation of H4K16 by acetylation is a priori not essential for the regulation of gene expression and the chromatin folding that occurs during development of the zygote. Second, unlike in females, only H4Q16 but not H4R16 chromatin supports development of male embryos into adults. This difference between males and females directly supports the critical role of H4K16 acetylation for dosage compensation in males. Third, cells with H4A16 chromatin are viable, proliferate, and can differentiate to form normal tissues in both males and females, but animals that entirely consist of cells with H4A16 chromatin arrest development at the end of embryogenesis. This lethality contrasts with the viability of animals with H4K16, H4R16, or H4Q16 chromatin and suggests that presence of a long aliphatic side chain with a polar group (i.e., either K, R, or Q) at residue 16 is more important for H4 function than the ability to regulate the charge of this residue by acetylation. A fourth main conclusion of this work comes from the finding that males that completely lack Mof protein (i.e., mof m-z- males) arrest development during gastrulation, whereas females of the same genotype develop into morphologically normal adults. This uncovers a previously unknown critical requirement of Mof acetyltransferase activity in males, already during the onset of zygotic gene transcription. The following sections discuss the results reported in this study in the context of the current understanding of the role of H4K16 and its acetylation (Copur, 2018).

In yeast and flies, the comparison of the severities of the phenotypes caused by different amino acid substitutions at H4K16 highlights how the two organisms have evolved to use this conserved residue and its modification in different ways. In yeast, H4K16ac is present genome-wide and SIR silencing is the key physiological process that requires H4K16, in its deacetylated state. Yeast cells with H4K16R, H4K16Q, or H4K16A mutations are viable but they show defective SIR silencing. Silencing is much more strongly impaired in H4K16Q or H4K16A mutants than in H4K16R mutants. This is because SIR3 protein binding to deacetylated H4K16, a prerequisite for silencing, is probably less severely impaired by the arginine substitution than by the alanine or glutamine substitutions. In Drosophila, the phenotypic differences between H4K16R, H4K16Q, and H4K16A mutants suggest that H4K16 is associated with two other, distinct physiological functions that are critical for the organism. The male-specific lethality of H4K16R mutants and the restoration of male viability in H4K16Q mutants demonstrate that dosage compensation is one essential process that critically requires the acetylated form of H4K16. A reduction of internucleosomal contacts by H4K16ac to generate chromatin that is more conducive to gene transcription on the male X chromosome currently is the simplest mechanistic explanation for how H4K16 acetylation enables dosage compensation. The observation that an H4K16A mutation causes lethality in both sexes suggests that, unlike in yeast, a long aliphatic side chain at this residue is essential for H4 function in Drosophila. It is currently not known why Drosophila H4K16A mutants die. However, it is important to note that H4K16A mutant cells retain the capacity to proliferate and differentiate and the mutation therefore does not disrupt any fundamental process required for cell survival (Copur, 2018).

Previous studies that investigated the function of histone H3 modifications by histone replacement genetics showed that for modifications associated with transcriptionally active chromatin it is essential to remove not only the wild-type copies of the canonical histone genes but to also mutate the histone H3.3 variants. The analyses of H4K16R, H4K16Q, and H4K16A mutant phenotypes reported in this study were all performed in the genetic background of animals lacking His4r, the only histone H4 variant in Drosophila. Importantly, it was found that in a His4r+ background, where only the canonical H4 proteins are replaced with mutant H4, the modifiable His4r protein permitted H4K16R His4r+ mutant males and, surprisingly, also H4K16A His4r+ mutant females and males to develop into adults. These animals were therefore not analyzed further. Supporting these observations, a recent study that used a similar strategy for replacing canonical histone H4 with H4K16R also found that H4K16R His4r+ mutant males develop into normal adults. This suggests that, like His3.3, the His4r protein might also preferentially be incorporated into transcriptionally active chromatin and become acetylated by Mof. Although the viable H4K16R His4r+ males have been reported to show a significant reduction of X-linked gene expression, a full assessment of transcriptional defects in animals containing only H4R16 nucleosomes would require that such molecular analyses be performed in H4K16R His4rΔ mutant males (Copur, 2018).

A final point that should be noted here is that during the early stages of embryogenesis, H4K16R, H4K16Q, or H4K16A mutants also still contain maternally deposited wild-type H4 protein that becomes incorporated into chromatin during the preblastoderm mitoses and only eventually becomes fully replaced by mutant H4 proteins during postblastoderm cell divisions. During the earliest stages of embryogenesis it has therefore not been possible to assess the phenotype of animals with chromatin containing exclusively H4R16, H4Q16, or H4A16 nucleosomes. This needs to be kept in mind when considering comparisons between the phenotypes of H4K16 point mutants and mof m-z- mutants (Copur, 2018).

Males without Mof protein (i.e., mof m-z- males) arrest development during gastrulation while their female siblings develop into adults. Moreover, mof m-z+ males also fail to develop, demonstrating that zygotic expression of Mof protein is insufficient to rescue male embryos that lacked maternally deposited Mof protein. The most straightforward explanation for these observations is that H4K16 acetylation by Mof is critically required for hypertranscription of X-chromosomal genes that has been reported to occur already during the onset of zygotic gene transcription and that the early developmental arrest of males is a direct consequence of failed dosage compensation (Copur, 2018).

How does this early requirement for Mof activity at the blastoderm stage relate to current understanding of the temporal requirement for the DCC for dosage compensation? Previous studies showed that males lacking the DCC subunits Msl-1, Msl-2, Msl-3, or Mle complete embryogenesis and arrest development much later, around the stage of puparium formation. For example, Msl-1 protein null mutants (i.e., msl-1 m-z- mutants) die as late third instar larvae, yet Msl-1 directly interacts with Mof to incorporate it into the DCC and is critical for targeting the complex and H4K16ac accumulation on the X chromosome in larvae. One possible explanation for the conundrum that the lack of Mof but not that of Msl-1 or other DCC subunits results in lethality during gastrulation could be that during these early stages, H4K16 acetylation by Mof for dosage compensation is not as strictly dependent on the other DCC subunits as during later developmental stages, or that there is redundancy between Msl-1, Msl-2, or Msl-3 for targeting Mof to the X chromosome in the early embryo (Copur, 2018).

A final point worth noting is that Mof is also present in another protein assembly called the NSL complex. NSL was reported to act genome-wide for regulating housekeeping gene transcription in both sexes and several NSL subunits are essential for Drosophila viability. The finding that mof m-z- mutant females develop into morphologically normal adults shows that the NSL complex must exert regulatory functions that are essential for viability independently of Mof H4K16 acetyltransferase activity (Copur, 2018).

The acetylation of lysine residues in the N termini of histones is generally associated with chromatin that is conducive to gene transcription. Mutational studies in yeast showed that there is substantial functional redundancy between most of the different acetylated lysine residues in the N termini of histone H3 and H4 but that H4K16 has unique effects on transcriptional control, with well-defined phenotypic consequences. This study shows that in Drosophila the principal function of H4K16 acetylation is X-chromosome dosage compensation in males (Copur, 2018).


GENE STRUCTURE

Exons - 1


PROTEIN STRUCTURE

Amino Acids - 827

Structural Domains

A striking similarity exists between the MOF protein and Tip60, a recently identified human protein that appears to interact with the HIV-1 Tat transactivator. Discovered by means of the yeast two-hybrid selection system, Tip60 has been demonstrated to greatly enhance Tat transactivation of the HIV-1 promoter in transient expression assays (Kamine, 1996). MOF also displays extended amino acid homology to MOZ, the human monocytic leukemia zinc finger protein. The MOZ gene was recently identified as one of the two breakpoint-associated genes in the translocation found in the M4/M5 subtype of acute myeloid leukemia. The chromosome translocation fuses MOZ in-frame to CBP, the CREB transcriptional factor-binding protein (Borrow, 1996). Finally, a significant level of sequence similarity is found between MOF, the SAS2 and SAS3 gene products of Saccharomyces cerevisiae, and other proteins of as yet unidentified function. In yeast, SAS2 is involved in silencing the telomeres; SAS2 and, to a lesser extent SAS3, are also involved in HMR locus silencing (Reifsnyder, 1996). Present within this region of homology, which extends for ~250 amino acids, is a domain common to many acetyl transferases that has been shown to be required for the binding of acetyl coenzyme A. Deduced from its homology to mammalian spermidine/spermine acetyl transferases and microbial antibiotic acetyl transferases, this domain is also found in enzymes known to acetylate histones, such as histone acetyl transferase 1 of yeast, histone acetyl transferase A of Tetrahymena and its yeast homolog Gcn5p, and p300/CBP-associated factor P/CAF. A second domain, identified as a C2HC/H zinc finger found in a variety of transcription factors and in oncogenes, is present in all of the MOF-related proteins, with the exception of ScYOR244w. An additional region of homology is shared by MOF, Tip60 and the S.cerevisiae YOR244w. This region is very similar to the chromo domain contained within a large number of proteins. With respect to this domain, the highest level of similarity with MOF is exhibited by human retinoblastoma-binding proteins RBP-1 and RBP-2 and the frog XNF7 and newt PwA33 nuclear factors. The latter is a maternal protein associated with nascent transcripts on the lampbrush chromosome loops of the oocyte. The chromo-like domain and the single zinc finger may represent sites of protein-protein interaction, although binding to DNA should not necessarily be ruled out (Hilfiker, 1997).


males absent on the first: Evolutionary Homologs | Regulation | Developmental Biology | References

date revised: 15 May 2000

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