Disease relevance of msl-2

• We mapped the recruitment activity to a 217 bp roX1 fragment that shows male-specific DNase hypersensitivity and can be preferentially cross-linked in vivo to the MSL complex [1].

High impact information on msl-2

• Female flies must inhibit msl-2 mRNA translation for survival, and this inhibition is mediated by Sex-lethal (SXL) binding to sites in both the 5' and the 3' untranslated regions (UTRs) [2].
• A dual inhibitory mechanism restricts msl-2 mRNA translation for dosage compensation in Drosophila [2].
• The multisubunit MSL dosage compensation complex binds to hundreds of sites along the Drosophila single male X chromosome, mediating its hypertranscription [3].
• Consistent with the formation of a dosage compensation protein complex, msl-2 colocalizes with the other MSL proteins on the male X chromosome and coimmunoprecipitates with msl-1 from male larval extracts [4].
• In this neo-X chromosome, the pattern of MSL binding correlates with the known pattern of dosage compensation [5].

Biological context of msl-2

• Expression of msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila [4].
• An intron present at the 5' untranslated region (UTR) of msl-2 mRNA contains putative SXL binding sites and is retained in female flies [6].
• We also used three strains that carried constitutive transgenes of msl-2 with mutations in the 5' untranslated regions [7].
• The encoded protein (MSL-2) consists of 769 amino acid residues and has a RING finger (C3HC4 zinc finger) and a metallothionein-like domain with eight conserved and two non-conserved cysteines [8].
• A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16 [9].

Anatomical context of msl-2

• MSL-2 lacks a maternal component, and male-specific zygotic expression is detectable at the end of blastoderm [10].
• These results reveal an unexpected physical and functional connection between nuclear pore components and chromatin regulation through MSL proteins, highlighting the role of nucleoporins in gene regulation in higher eukaryotes [11].
• Here, we report the purification of enzymatically active MSL complexes from Drosophila embryos, Schneider cells, and human HeLa cells [11].
• This distribution pattern has been interpreted as a reflection of the tissue-specific transcriptional activity of the larval salivary gland and as an indication that the MSL complex associates with active chromatin [12].
• We observed that MLE is the only MSL expressed in the male germ cells and it is not localized to the X chromosome [13].

Associations of msl-2 with chemical compounds

• Male-specific lethal 2, a dosage compensation gene of Drosophila, undergoes sex-specific regulation and encodes a protein with a RING finger and a metallothionein-like cysteine cluster [8].
• Although UNR is present in both male and female flies, binding of SXL to uridine-rich sequences in the 3' untranslated region (UTR) of msl-2 mRNA recruits UNR to adjacent regulatory sequences, thereby conferring a sex-specific function to UNR [14].
• We propose 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 [15].
• X chromosome binding also requires a conserved leucine zipper-like motif that binds to MSL2 [15].

Physical interactions of msl-2

• The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex specifically regulated by Sex-lethal [16].

Regulatory relationships of msl-2

• We also provide evidence that the repression of MSL-2 is directly regulated by Sex-lethal at the level of translation [17].

Other interactions of msl-2

• In addition, msl-2 is required for translation and/or stability of MSL-1 in males [18].
• Our observations suggest that MSL-2 may be the target of the master regulatory gene Sxl and provide the basic elements of a working hypothesis on the function of MSL-2 in mediating the 2-fold increase in transcription that is characteristic of dosage compensation [8].
• We also used site-directed mutagenesis to determine the importance of the MSL-2 RING finger domain and second cysteine-rich motif [19].
• 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 [20].
• These mutations are the male-specific lethals msl-1, msl-2, and mle, which have been analyzed in the somatic tissues [21].

Analytical, diagnostic and therapeutic context of msl-2

• Utilizing chromatin immunoprecipitation, we have determined that H4Ac16 is present along the entire length of X-linked genes targeted by the MSL complex with relatively modest levels of acetylation at the promoter regions and high levels in the middle and/or 3' end of the transcription units [22].

References