male-specific lethal 1: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References
Gene name - male-specific lethal 1

Synonyms -

Cytological map position- 36F11-37A1

Function - chromatin protein

Keywords - dosage compensation

Symbol - msl-1

FlyBase ID: FBgn0005617

Genetic map position - 2-20

Classification - basic motif, leucine zipper-like motif, glycine-rich motif

Cellular location - nuclear



NCBI links: Precomputed BLAST | EntrezGene


Recent literature
Chlamydas, S., et al. (2016). Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation. Nat Struct Mol Biol [Epub ahead of print]. PubMed ID: 27183194
Summary:
Proper gene expression requires coordinated interplay among transcriptional coactivators, transcription factors and the general transcription machinery. This study reports that MSL1, a central component of the dosage compensation complex in Drosophila melanogaster and Drosophila virilis, displays evolutionarily conserved sex-independent binding to promoters. Genetic and biochemical analyses reveal a functional interaction of MSL1 with CDK7, a subunit of the Cdk-activating kinase (CAK) complex of the general transcription factor TFIIH. Importantly, MSL1 depletion leads to decreased phosphorylation of Ser5 of RNA polymerase II. In addition, it was demonstrated that MSL1 is a phosphoprotein, and transgenic flies expressing MSL1 phosphomutants show mislocalization of the histone acetyltransferase MOF and histone H4 K16 acetylation, thus ultimately causing male lethality due to a failure of dosage compensation. It is proposed that, by virtue of its interaction with components of the general transcription machinery, MSL1 exists in different phosphorylation states, thereby modulating transcription in flies.
Harumoto, T., Anbutsu, H., Lemaitre, B. and Fukatsu, T. (2016). Male-killing symbiont damages host's dosage-compensated sex chromosome to induce embryonic apoptosis. Nat Commun 7: 12781. PubMed ID: 27650264
Summary:
Some symbiotic bacteria are capable of interfering with host reproduction in selfish ways. How such bacteria can manipulate host's sex-related mechanisms is of fundamental interest encompassing cell, developmental and evolutionary biology. This study uncovered the molecular and cellular mechanisms underlying Spiroplasma-induced embryonic male lethality in Drosophila melanogaster. Transcriptomic analysis reveals that many genes related to DNA damage and apoptosis are up-regulated specifically in infected male embryos. Detailed genetic and cytological analyses demonstrate that male-killing Spiroplasma causes DNA damage on the male X chromosome interacting with the male-specific lethal (MSL) complex. The damaged male X chromosome exhibits a chromatin bridge during mitosis, and bridge breakage triggers sex-specific abnormal apoptosis via p53-dependent pathways. Notably, the MSL complex is not only necessary but also sufficient for this cytotoxic process. These results highlight symbiont's sophisticated strategy to target host's sex chromosome and recruit host's molecular cascades toward massive apoptosis in a sex-specific manner.
BIOLOGICAL OVERVIEW

In Drosophila melanogaster, X chromosome dosage compensation is achieved by doubling the transcription of most X-linked genes. The male-specific lethal (MSL) complex is required for this process and binds to hundreds of sites on the male X chromosome. The MSL1 protein is essential for X chromosome binding and serves as a central scaffold for MSL complex assembly. The amino-terminal region of MSL1 binds to hundreds of sites on the X chromosome in normal males but only to approximately 30 high-affinity sites in the absence of endogenous MSL1. Binding to the high-affinity sites requires a basic motif at the amino terminus that is conserved among Drosophila species. X chromosome binding also requires a conserved leucine zipper-like motif that binds to MSL2. A glycine-rich motif between the basic and leucine-zipper-like motifs mediates MSL1 self-association in vitro and binding of the amino-terminal region of MSL1 to the MSL complex assembled on the male X chromosome. It is proposed that the basic region may mediate DNA binding and that the glycine-rich region may promote the association of MSL complexes to closely adjacent sites on the X chromosome (Li, 2005).

Significant progress has been made in understanding the regulation of transcription of individual genes in eukaryotes. It has also become apparent that the transcription of many genes within a particular region of a chromosome can be cocoordinately regulated by mechanisms that involve changes in the local chromosome structure. The most dramatic example of this is X chromosome dosage compensation, the equalization of X-linked gene transcription between XY males and XX females. In mammals, this is achieved by compacting one X chromosome in females into an inactive heterochromatic structure. In Drosophila melanogaster, the male X chromosome is modified to a more open structure that somehow leads to a precise doubling of transcription of nearly all the predicted 2,240 X-linked genes (Li, 2005 and references therein).

Dosage compensation in Drosophila requires the ribonucleoprotein male-specific lethal (MSL) complex. The complex binds to hundreds of sites along the male X chromosome. The core protein components are MSL1, MSL2, MSL3, MLE, and MOF. Loss-of-function mutations in any of the genes encoding these proteins lead to male-specific lethality, due to a failure in dosage compensatation. A sixth protein, JIL1, preferentially associates with the male X chromosome and has been shown to coimmunoprecipitate with components of the MSL complex. Loss-of-function jil1 mutations are, however, lethal to both sexes, indicating a vital role for JIL1 in addition to X chromosome dosage compensation. The two noncoding RNA components of the complex, roX1 and roX2, share little sequence similarity but are genetically redundant and appear to be functionally interchangeable. The MSL complex does not assemble in females since one protein component, MSL2, is absent (Li, 2005).

MSL1 plays a central role in assembly of the MSL complex (Scott, 2000). The amino-terminal domain of MSL1 binds to MSL2 (Copps, 1998, Scott, 2000). It has been suggested that the interaction between MSL1 and MSL2 was via predicted amphipathic coiled-coil α-helical regions that are found within the interacting domains (Scott, 2000). In addition, the carboxyl-terminal domain of MSL1 binds to both MSL3 and MOF (Scott, 2000). Subsequent studies have shown that MOF and MSL3 bind to adjacent regions in the MSL1 carboxyl-terminal domain (Morales, 2004). Further, formation of the MSL1/MSL3/MOF complex leads to a significant increase in the histone acetylase activity of MOF (Morales, 2004), which preferentially acetylates histone H4 at lysine 16. Both MSL3 and MOF have been shown to bind RNA nonspecifically in vitro and thus may have a role in incorporation of roX RNAs into the complex (Akhtar, 2000). Incorporation of MLE into the complex is presumably via interaction with the roX RNA, since MLE contains an RNA binding domain but does not appear to interact (Copps, 1998) with any of the other protein components of the complex (Li, 2005).

While progress has been made in understanding MSL complex assembly, how the complex specifically binds to hundreds of sites on the male X chromosome and then upregulates transcription so precisely remains poorly understood. One model for X chromosome binding is that the first step involves recognition of approximately 30 'high-affinity' or 'chromatin entry' sites on the X chromosome by the MSL1/MSL2 dimeric complex (Kageyama, 2001). Additional binding to the high-affinity sites within the roX1 and roX2 genes requires MLE. Subsequently, the other components bind, and the complex then spreads along the chromosome to hundreds of other sites. One of the key observations that support this model is that the MSL1/MSL2 complex binds to the high-affinity sites in the absence of MSL3, MLE, or MOF (Gu, 1998, Lyman, 1997). MSL1 and MSL2, however, do not contain any of the well-characterized DNA binding domains. Previously it was found that a deletion mutant of MSL1 that lacks the first 84 amino acids (aa) binds to MSL2, MSL3, and MOF but fails to bind to the X chromosome (Scott, 2000). This result suggested an important role for the amino-terminal region in X chromosome binding. This study shows that a conserved basic segment at the amino terminus of MSL1 is essential for binding to the high-affinity sites on the X chromosome in the absence of endogenous MSL1. It was also found that the adjacent region of MSL1 mediates MSL1 self-association. Lastly, the importance of the predicted coiled-coil region of MSL1 in binding to MSL2 was confirmed and that this interaction was shown to be essential for binding of the amino-terminal region of MSL1 to the X chromosome (Li, 2005).

It is almost 14 years since the first report that a component of the MSL complex selectively binds to hundreds of sites on the male X chromosome (Kuroda, 1991). Although neither MSL1 nor MSL2 has a readily identifiable DNA binding domain, both are essential for binding to the high-affinity sites on the X chromosome (Lyman, 1997). This study shows that a conserved basic motif at the amino terminus of MSL1 is required for binding to high-affinity sites. Short stretches of basic amino acids are involved in DNA recognition by basic leucine zipper (bZIP) and basic helix-loop-helix proteins. By analogy, a possible role for the basic region of MSL1 is to recognize a DNA sequence within the ~30 high-affinity sites on the male X chromosome. Consistent with this possibility, it was found that replacement of three of the conserved basic amino acids at positions 3, 4, and 6 by alanine eliminated binding of the amino-terminal region of MSL1 to all but five of the high-affinity X chromosome binding sites. Two of the five sites mapped to the location of the roX genes (roX1 at 3F and roX2 at 10C). It is possible that binding to these sites could be via association with the RNA components of the complex rather than via DNA recognition. Two conserved aromatic amino acids in the basic region appear to be important for binding specificity, since alanine substitution leads to increased binding to the autosomes. Aromatic and nonpolar amino acids in the basic domain of bZIP protein C/EBPα are important for DNA recognition and binding specificity, respectively. Investigating these possibilities will require in vitro binding studies with DNA sequences from the three high-affinity sites that have been identified. It is also possible that the amino terminus of MSL1 could bind RNA, since several proteins bind to RNA via basic-rich motifs. If so, the MSL1/MSL2 complex would associate with the nascent RNA of genes transcribed within the high-affinity sites. However, binding of MSL1 to the X chromosome is not disrupted by RNaseA treatment (Buscaino, 2003). This suggests that it is more likely that the MSL1/MSL2 heteromeric complex recognizes DNA sequences within the high-affinity sites (Li, 2005).

bZIP and basic helix-loop-helix proteins bind to DNA as dimers with bZIP dimers, forming coiled coil structures. Coiled coil domains contain a heptad repeat of the form (a-b-c-d-e-f-g)n, where positions a and d are commonly occupied by apolar residues. Oligomerization then occurs through the formation of a multistranded, α-helical coiled coil in which a and d residues become internalized and hence shielded from the aqueous environment. It has been proposed that the short heptad substructures observed in the sequences of both MSL1 and MSL2 (residues 128 to 143 and 25 to 40, respectively) could provide a simple means by which chain dimerization could be effected in vivo (Scott, 2000). This study identified highly conserved apolar regions that lay immediately N terminal to the heptad motif in both chains (residues 113 to 121 and 5 to 14, respectively). Alanine substitution of four amino acids in the MSL1 apolar region eliminated binding to MSL2 in vitro and in vivo. A possible explanation for the critical importance of the MSL1 apolar region is that this acts as a trigger motif that facilitates coiled-coil formation. In the case of long heptad-containing regions, trigger motifs are sometimes used in the sequence to provide a short length of highly stable coiled coil that acts as a nucleating point for subsequent coiled-coil formation. For short lengths of coiled coil, however, other features may play an important role in either stabilizing or facilitating the formation of coiled-coil structure. If the apolar region of MSL1 does serve as a trigger for dimerization, then the first turn of the α-helix would be expected to be important in zipping together the two proteins. Consistent with this suggestion, it was found alanine substitution of the first two apolar amino acids in the a position and of the charged amino acids in the e and g positions of the first heptad decreased binding to MSL2 in vitro. It should also be noted that the RING finger domain of MSL2, which immediately follows the short heptad motif, is also important for binding (Copps, 1998) to MSL1 (Li, 2005).

Remarkably, it was found that the amino-terminal domain of MSL1 lacking the basic motif (Δ26HA) binds to all sites on the male X chromosome. This appears to be because Δ26HA binds to full-length MSL1 incorporated into the complete MSL complex. It was found that a glycine-rich region between the basic and coiled-coil motifs facilitated MSL1 self-association in vitro and binding to the MSL complex in vivo. The glycine-rich and leucine zipper-like motifs appear to function independently, as MSL1 self-association does not require MSL2 and deletion of the glycine-rich motif (e.g., Δ84HA) does not disrupt binding to MSL2. However, binding to the MSL complex in vivo does require interaction with MSL2; a mutation (mut_apo) that disrupts binding of MSL1 to MSL2 in vitro also eliminates binding to the male X chromosome, despite containing a complete glycine-rich motif. An explanation for these observations is that the MSL1NHA:MSL2 heterodimer binds to sites on the X chromosome immediately adjacent to sites occupied by the endogenous MSL complex and that the binding is stabilized by association of MSL1NHA with MSL1 in the complex. The 18D10 high-affinity site appears to consist of a cluster of sites of intermediate or weak affinity for the MSL complex. It is likely that stable binding to the X chromosome involves some cooperativity between MSL complexes bound to adjacent sites of differing affinity. MSL1 self-association may then be important in cooperative binding of MSL complexes to the male X chromosome, but testing this proposal will require evaluation of a series of alanine substitution mutations within the glycine-rich region. Alternatively, the results do not preclude the possibility that MSL1NHA is recruited to the male X chromosome by interaction with both MSL2 and MSL1 in prebound MSL complex. Interaction with MSL1 in the complex must also be necessary, since Δ84HA does not bind to MSL1 or male X chromosome, yet binds to MSL2 (Li, 2005).

Modulation of heterochromatin by male specific lethal proteins and roX RNA in Drosophila melanogaster males

The ribonucleoprotein Male Specific Lethal (MSL) complex is required for X chromosome dosage compensation in Drosophila males. Beginning at 3 h of development the MSL complex binds transcribed X-linked genes and modifies chromatin. A subset of MSL complex proteins, including MSL1 and MSL3, is also necessary for full expression of autosomal heterochromatic genes in males, but not females. Loss of the non-coding roX RNAs, essential components of the MSL complex, lowers the expression of heterochromatic genes and suppresses position effect variegation (PEV) only in males, revealing a sex-limited disruption of heterochromatin. MLE, but not Jil-1 kinase, was found to contribute to heterochromatic gene expression. To determine if identical regions of roX RNA are required for dosage compensation and heterochromatic silencing, a panel of roX1 transgenes and deletions was tested; the X chromosome and heterochromatin functions were found to be separable by some mutations. Widespread autosomal binding of MSL3 occurs before and after localization of the MSL complex to the X chromosome at 3 h AEL. Autosomal MSL3 binding was dependent on MSL1, supporting the idea that a subset of MSL proteins associates with chromatin throughout the genome during early development. It is postulated that this binding may contribute to the sex-specific differences in heterochromatin that have been noted (Koya, 2015).

A central question raised by this study is how factors known for their role in X chromosome dosage compensation also modulate autosomal heterochromatin. Although the MSL proteins were first identified by their role in X chromosome compensation, homologues of these proteins participate in chromatin organization, DNA repair, gene expression, cell metabolism and neural function throughout the eukaryotes. Furthermore, flies contain a distinct complex, the Non-Sex specific Lethal (NSL) complex, containing MOF and the MSL orthologs NSL1, NSL2 and NSL3. The essential NSL complex is broadly associated with promoters throughout the fly genome, where it acetylates multiple H4 residues. In light of the discovery that the MSL proteins represent an ancient lineage of chromatin regulators, it is unsurprising that members of this complex fulfill additional functions (Koya, 2015).

An alternative hypothesis for the dosage compensation of male X-linked genes proposes that the MSL proteins are general transcription regulators, and recruitment of these factors to the male X chromosome reduces autosomal gene expression, thus equalizing the X:A expression ratio. Arguing against this idea are ChIP studies finding that the MSL complex, and engaged RNA polymerase II, are increased within the bodies of compensated X-linked genes. In agreement with this, a study that normalized expression to genomic DNA concluded that compensation increases the expression of male X-linked genes. The current study now reveals that autosomal heterochromatic genes are indeed dependent on a subset of MSL proteins for full expression. However, native heterochromatic genes make up only 4% of autosomal genes, and their misregulation is not expected to compromise genome-wide expression studies normalized to autosomal expression (Koya, 2015).

Expression of heterochromatic genes is thought to involve mechanisms to overcome the repressive chromatin environment. It is possible that a complex composed of roX RNA and a subset of MSL proteins participates in this process. This would explain why heterochromatic genes are particularly sensitive to the loss of these factors. Alternatively, it is possible that roX and MSL proteins participate in heterochromatin assembly. This would explain the simultaneous disruption of heterochromatic gene expression and suppression of PEV at transgene insertions (Koya, 2015).

Heterochromatin assembly is first detected at 3-4 h AEL, a time when MSL3 is bound throughout the genome. Intriguingly, studies from yeast identify a role for H3K4 and H4K16 acetylation in formation of heterochromatin. Active deacetylation of H4K16ac is necessary for spreading of chromatin-based silencing in yeast, demonstrating the need for a sequential and ordered series of histone modifications (Koya, 2015).

As MOF is responsible for the majority of H4K16ac in the fly, a MOF-containing complex could fulfill a similar role during heterochromatin formation. While this study found a significant effect of MOF in expression only on the X and 4th chromosomes, it is possible that examination of a larger number of genes would reveal a more widespread autosomal effect (Koya, 2015).

In roX1 roX2 males the 4th chromosome displays stronger suppression of PEV and more profound gene misregulation than do other heterochromatic regions. This is consistent with the observation that heterochromatin on the 4th chromosome is genetically and biochemically different from that on other chromosomes. Loss of roX RNA leads to misregulation of genes in distinct genomic regions, the dosage compensated X chromosome and autosomal heterochromatin. This study found that the regulation of these two groups is, to some extent, genetically separable. MSL2, which binds roX1 RNA and is an essential member of the dosage compensation complex, is not required for full expression of heterochromatic genes in males. Ectopic expression of MSL2 in females induces formation of MSL complexes that localize to both X chromosomes, inducing inappropriate dosage compensation. As would be expected from the lack of a role for MSL2 in autosomal heterochromatin in males, ectopic expression of this protein in females has no effect on PEV (Koya, 2015).

Elegant, high-resolution studies reveal that MLE and MSL2 bind essentially indistinguishable regions of roX1. Three prominent regions of MLE/MSL2 binding have been identified, one overlapping the 3' stem loop. This stem loop incorporates a short 'roX box' consensus sequence that is present in D. melanogaster roX1 and roX2, and conserved in roX RNAs in related species (Koya, 2015).

An experimentally supported explanation for the concurrence of MLE and MSL2 binding at the 3' stem loop is that MLE, an ATP-dependent RNA/DNA helicase, remodels this structure to permit MSL2 binding. The finding that disruption of this stem blocks dosage compensation but does not influence heterochromatic integrity is consistent with participation of roX1 in two processes that differ in MSL2 involvement. However, a region surrounding the stem loop is required for the heterochromatic function of roX1, as roX1Δ10, removing the stem loop and upstream regions, is deficient in both dosage compensation and heterochromatic silencing. Further differentiating these processes is the finding that low levels of roX RNA from a repressed transgene fully rescue heterochromatic silencing, but not dosage compensation. An intriguing question raised by this study is why the sexes display differences in autosomal heterochromatin (Koya, 2015).

The chromatin content of males and females are substantially different as XY males have a single X and a large, heterochromatic Y chromosome. It is speculated that this has driven changes in how heterochromatin is established or maintained in one sex. A search for the genetic regulators of the sex difference in autosomal heterochromatin eliminated the Y chromosome and the conventional sex determination pathway, suggesting that the number of X chromosomes determines the sensitivity of autosomal heterochromatin to loss of roX activity. Interestingly, the amount of pericentromeric X heterochromatin, rather than the euchromatic 'numerator' elements, appears to be the critical factor. The recognition that heterochromatin displays differences in the sexes, and that a specific set of proteins are required for normal function of autosomal heterochromatin in males suggests a useful paradigm for the evolution of chromatin in response to genomic content (Koya, 2015).


GENE STRUCTURE

cDNA clone length - 4644

Exons - 2

Bases in 3' UTR - 1522

PROTEIN STRUCTURE

Amino Acids - 1039

Structural Domains and Evolutionary Homolog

Male-specific lethal-one (msl-1) is one of four genes that are required for dosage compensation in Drosophila males. To determine the molecular basis of msl-1 regulation of dosage compensation, the gene was cloned and its products characterized. The Msl-1 protein has no significant similarity to proteins in the current data bases, but contains an acidic N terminus characteristic of proteins involved in transcription and chromatin modeling. Evidence is presented that the Msl-1 protein is associated with hundreds of sites along the length of the X chromosome in male, but not in female, nuclei. These findings support the hypothesis that Msl-1 plays a direct role in increasing the level of X-linked gene transcription in male nuclei (Palmer, 1993: full text of paper).

Genetic screens designed to isolate mutations affecting essential biochemical or physiological processes unique to males or females have uncovered several sex-specific lethal mutations that affect dosage compensation. Among these mutations are four male-specific lethals, male-specfic lethal-1 (msl-1), male-specific lethal-2 (Belote, 1980), maleless on the third (msl-3) and maleless collectively called the msls. The products of the msl genes are necessary to set and/or maintain an equivalent level of most X-linked gene transcripts in males relative to females. All loss of function msl mutations exert their lethal effects during late larval development in males but have no detectable effects in females. The null phenotypes of the four msls are roughly equivalent, even in multiply mutant combinations. The only discernable differences are slight maternal effects associated with msl-1 and mle (Belote, 1980) and the requirement for mle in male germline development. Therefore, it has been difficult to determine if epistatic relationships exist among these genes using classical genetics (Palmer, 1993).

The most striking feature of the deduced Msl-1 protein sequence is the presence of two highly acidic stretches in the N terminus that are composed almost entirely of aspartic or aspartic and glutamic acids (amino acids 95-102 and 283-307). Comparison of the predicted Msl-1 protein sequence with sequences in the GenBank data bases shows that these acidic motifs are similar to those found in a diverse group of nuclear proteins involved in transcription and chromatin modeling. The N terminus of Msl-1 also contains a series of interspersed glutamic acid doublets which contribute to the acidic nature of this region of the protein (25% glutamic or aspartic acid). The acidic nature of the N terminus is, to a lesser degree, similar to the acidic activation domains found in some transcription factors. However, the tight clustering of the Asp/Glu residues makes it unlikely that this region could form an amphipatic helix characteristic of acidic activation domains. Outside of the Asp/Glu clusters, msl-1 displays no significant similarities to other proteins, nor does it contain motifs characteristic of DNA binding proteins. Further analysis of the putative msl-1 protein revealed over 40 potential phosphorylation sites as well as four potential N-glycosylation sites. The internal region of the protein (amino acids 646-704) is particularly rich in serine, threonine, and proline residues. Within a 35 amino acid stretch, 251 35 residues are either proline, serine, or threonine. Several of these groupings form S/T-P motifs which are often substrates for the cdc 2 family of protein kinases. Therefore, it is possible that phosphorylation could contribute to the regulation of Msl-1 activity (Palmer, 1993).

Using standard bioinformatics methods, sequences encoding probable homologs of Drosophila melanogaster MSL1 in the completed genome of Drosophila pseudoobscura and in the draft genomes of five other Drosophila species were compared. An alignment of the amino-terminal domain sequences of the seven MSL1 sequences shows the greatest similarity is between the D. melanogaster MSL1 sequence and MSL1 sequences from the closely related species Drosophila simulans, Drosophila yakuba, and Drosophila erecta. However, there is also significant similarity with Drosophila pseudoobscura and Drosophila virilis MSL1s, which are more distantly related to D. melanogaster. Two well-conserved regions were apparent from the alignment. Eight of the first 16 amino acids are identical in all Drosophila MSL1s. In particular, the basic and aromatic amino acids are highly conserved. The predicted coiled-coil region (aa 96 to 159 of D. melanogaster) is also highly conserved. The region between the two conserved regions (aa 16 to 95) has few amino acids that are identical but is enriched for glycine, proline, histidine, and asparagine (Li, 2005).

Dosage compensation in Drosophila is mediated by a complex, called compensasome, composed of at least five proteins and two noncoding RNAs. Genes encoding compensasome proteins have been collectively named male-specific lethals or msls. Recent work showed that three of the Drosophila msls (msl-3, mof, and mle) have an ancient origin. This study describes likely orthologues of the two remaining msls, msl-1 and msl-2 in several invertebrates and vertebrates. The MSL-2 protein is the only one found in Drosophila and vertebrate genomes that contains both a RING finger and a peculiar type of CXC domain, related to the one present in Enhancer of Zeste proteins. MSL-1 also contains two evolutionarily conserved domains: a leucine zipper and a second characteristic region, described in this study for the first time, which has been called the PEHE domain. These two domains are present in the likely orthologues of MSL-1 as well as in other genes in several invertebrate and vertebrate species. Although it cannot be excluded that the compensasome complex is a recent evolutionary novelty, these results shows that all msls are found in mammals, suggesting that protein complexes related to the compensasome may be present in mammalian species. Metazoans that lack several of the msls, such as Caenorhabditis elegans, cannot contain compensasomes. The evolutionary relationships of the compensasome and the NuA4 complex, another chromatin-remodeling complex that contains related subunits, are discussed (Marin, 2003).

A stable, multisubunit human histone acetyltransferase complex (hMSL) contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. hMOF is a component of additional complexes, forming associations with host cell factor 1 and a protein distantly related to MSL1 (hMSL1v1). Two versions of hMSL3 were found in the hMSL complex that differ by the presence of the chromodomain. Lastly, it was found that reduction in the levels of hMSLs and acetylation of H4 at lysine 16 are correlated with reduced transcription of some genes and with a G2/M cell cycle arrest. This is of particular interest given the recent correlation of global loss of acetylation of lysine 16 in histone H4 with tumorigenesis (Smith, 2005; full text of article).

Hampin, homolog of Drosophila MSL1, is a partner of histone acetyltransferase MYST1/MOF. Functions of these proteins remain poorly understood beyond their participation in chromatin remodeling complex MSL. In order to identify new proteins interacting with hampin, a mouse cDNA library was screened in yeast two-hybrid system with mouse hampin as bait, and five high-confidence interactors were found: MYST1, TPR proteins TTC4 and KIAA0103, NOP17 (homolog of a yeast nucleolar protein) and transcription factor GC BP. Subsequently, all these proteins were used as baits in library screenings and more new interactions were found: tumor suppressor RASSF1C and spliceosome component PRP3 for KIAA0103, ring finger RNF10 for RASSF1C, and RNA polymerase II regulator NELF-C for MYST1. The majority of the observed interactions was confirmed in vitro by pull-down of bacterially expressed proteins. Reconstruction of a fragment of mammalian interactome suggests that hampin may be linked to diverse regulatory processes in the nucleus (Dmitriev, 2007).


male-specific lethal 1: Regulation | Developmental Biology | Effects of Mutation | References

date revised: 12 January 2007

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