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Posttranscriptional control of X‐chromosome dosage compensation

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Abstract RNA regulation plays a major role in the generation of diversity at the molecular and cellular levels, and furnishes the cell with flexibility potential to adapt to changing environments. Often, the regulation by/of RNA dictates when, where, and how the information encoded in the nucleus is revealed. One example is the regulation of X‐chromosome dosage compensation. In Drosophila, differences in X‐linked gene dosage between males and females are compensated by the transcriptional upregulation of the single male X chromosome. Mechanisms of alternative splicing and translational control, among others, enforce dosage compensation in males while inhibiting this process in females. In this review, we discuss the posttranscriptional RNA regulatory mechanisms that ensure appropriate dosage compensation in Drosophila, drawing parallels with the mammalian system when appropriate. WIREs RNA 2011 2 534–545 DOI: 10.1002/wrna.75 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes Translation > Translation Regulation RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development

Dosage compensation mechanisms in the three model organisms. According to the classical model, the single male X chromosome is hypertranscribed to adjust its expression to that of autosomes. Mammalian females inactivate one of the X chromosomes, while the active one is hypertranscribed. In hermaphrodites of Caenorhabditis elegans, expression from the two otherwise hyperactive X chromosomes is repressed by half. Hyperactive and inactive chromosomes are shown in green and red, respectively. Chromosomes suffering both activation and repression are shown in yellow.

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Posttranscriptional regulation of msl2 expression. (a) Mechanisms of splicing inhibition. The sequence landmarks of the intron are shown (see text for details). Sex‐lethal (SXL)‐binding sites are located in the proximity of the 5′ and 3′ splice sites, and are indicated in red. The 3′ SXL‐binding site coincides with the polypyrimidine tract. SXL competitively blocks TIA‐1 and U2AF binding to the 5′ and 3′ sites, respectively, leading to a failure in U1 and U2 snRNP recruitment. (b) Mechanism of translation inhibition. The translation initiation factors leading to closed‐loop formation [eukaryotic initiation factor (eIF)4G, eIF4E, and poly(A)‐binding protein (PABP)] are indicated. SXL binds to specific sites located in both the 5′ and 3′ untranslated regions (UTRs) of msl2 messenger RNA (mRNA). SXL bound to the 3′ UTR recruits upstream of N‐ras (UNR), which in turn contacts PABP and possibly other factors (X) leading to inhibition of 43S ribosomal complex recruitment (step 1). SXL bound to the 5′ UTR inhibits the scanning of 43S complexes that may have escaped the 3′ UTR‐mediated control (step 2).

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The RNA on the X (roX) genes and their RNA products. (a) Schematic representation of the major isoforms of roX1 and roX2 RNAs. The roX boxes are depicted in red, and the roX‐like boxes in pink. The black circle at the 5′ end of the RNAs represents the cap structure. The putative stem‐loops are indicated. (b) roX genes and transcript isoforms. The DNaseI hypersensitive sites (DHS) and the roX boxes are indicated in yellow and red, respectively. Introns are denoted as thin lines. Vertical arrows indicate alternative polyadenylation sites. E1–E3 denote the exons of roX2. The asterisk marks the major roX2 RNA isoform.

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Dosage compensation in Drosophila. (a) The composition of the dosage compensation complex (DCC) is shown, as well as the enzymatic activities associated to the complex (see text for details). In males, the DCC binds to hundreds of sites along the single X chromosome and promotes H4K16 acetylation. (b) In females, the repression of msl2 expression by sex‐lethal (SXL) inhibits DCC formation. In the absence of male‐specific lethal (MSL)2, MSL1 and the roX RNAs are unstable. The lower panels show the localization of the DCC on the X chromosomes of third instar salivary glands from male and female larvae, visualized by staining with anti‐MSL2 antibodies.

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Systematic analysis of posttranscriptional gene expression (WIREs WIREs Systems Biology and Medicine)

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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Processing > Splicing Regulation/Alternative Splicing
Translation > Translation Regulation
RNA in Disease and Development > RNA in Development

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