Abstract
The dosage compensation complex (DCC) binds to single X chromosomes in Drosophila males and increases the transcription level of X-linked genes by approximately twofold. Male-specific lethal 2 (MSL2) together with MSL1 mediates the initial recruitment of the DCC to high-affinity sites in the X chromosome. MSL2 contains a DNA-binding cysteine-rich CXC domain that is important for X targeting. In this study, we determined the solution structure of MSL2 CXC domain by NMR spectroscopy. We identified three zinc ions in the CXC domain and determined the metal-to-cysteine connectivities from 1H-113Cd correlation experiments. The structure reveals an unusual zinc-cysteine cluster composed of three zinc ions coordinated by six terminal and three bridging cysteines. The CXC domain exhibits unexpected structural homology to pre-SET motifs of histone lysine methyltransferases, expanding the distribution and structural diversity of the CXC domain superfamily. Our findings provide novel structural insight into the evolution and function of CXC domains.
Highlights
Organisms with different numbers of sex chromosomes between males and females face the problem of an unequal dosage of genes from sex chromosomes
This dosage compensation process is mediated by the dosage compensation complex (DCC) or male-specific lethal (MSL) complex, which contains at least five proteins MSL1, Male-specific lethal 2 (MSL2), MSL3, males absent on the first (MOF) and maleless (MLE) and two non-coding RNAs roX1 and roX2
The 1H-15N HSQC spectrum of the MSL2 CXC domain displays a single set of well-dispersed peaks, indicating that the fragment is autonomously folded and amenable for further structural characterization (Fig. 1A)
Summary
Organisms with different numbers of sex chromosomes between males and females face the problem of an unequal dosage of genes from sex chromosomes. In Drosophila melanogaster, the transcriptional level of most genes in the single male X chromosome is increased by approximately twofold to match that from two female X chromosomes (see recent reviews [1,2,3]). This dosage compensation process is mediated by the dosage compensation complex (DCC) or male-specific lethal (MSL) complex, which contains at least five proteins MSL1, MSL2, MSL3, males absent on the first (MOF) and maleless (MLE) and two non-coding RNAs roX1 and roX2. The transcriptional activation is caused, at least in part, by the MOF-mediated acetylation of histone H4 lysine 16 and enhanced transcriptional elongation [11]
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