Msl1-Mediated Dimerization of the Dosage Compensation Complex Is Essential for Male X-Chromosome Regulation in Drosophila

SummaryThe Male-Specific Lethal (MSL) complex regulates dosage compensation of the male X chromosome in Drosophila. Here, we report the crystal structure of its MSL1/MSL2 core, where two MSL2 subunits bind to a dimer formed by two molecules of MSL1. Analysis of structure-based mutants revealed that MSL2 can only interact with the MSL1 dimer, but MSL1 dimerization is MSL2 independent. We show that Msl1 is a substrate for Msl2 E3 ubiquitin ligase activity. ChIP experiments revealed that Msl1 dimerization is essential for targeting and spreading of the MSL complex on X-linked genes; however, Msl1 binding to promoters of male and female cells is independent of the dimer status and other MSL proteins. Finally, we show that loss of Msl1 dimerization leads to male-specific lethality. We propose that Msl1-mediated dimerization of the entire MSL complex is required for Msl2 binding, X chromosome recognition, and spreading along the X chromosome.

Graphical AbstractFigure optionsDownload high-quality image (165 K)Download as PowerPoint slideHighlights
► MSL1 and MSL2 form a tetrameric core of the MSL complex
► MSL1 dimerization enables MSL2 binding, X chromosome recognition, and spreading
► MSL1-mediated dimerization of MSL2 enhances its E3 ubiquitin ligase activity
► MSL1 binding to promoters is independent from its role in dosage compensation