A dual inhibitory mechanism restricts msl-2 mRNA translation for dosage compensation in Drosophila.
Drosophila MSL-2 is the limiting component of the dosage compensation complex. 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). Here, we uncover the mechanism by which SXL achieves tight control of translation initiation. SXL binding to the 3'UTR regulatory region inhibits the recruitment of 43S ribosomal preinitiation complexes to the mRNA. Ribosomal complexes escaping this block and binding to the 5' end of the mRNA are challenged by SXL bound to the 5'UTR, which interferes with scanning to the downstream initiation codon of the mRNA. This failsafe mechanism thus forms the molecular basis of a critical step in dosage compensation. The results also elucidate a two step principle of translational control via multiple regulatory sites within an mRNA.
Beckmann
Karsten
K
Gene Expression Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Grskovic
Marica
M
Gebauer
Fátima
F
Hentze
Matthias W
MW
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D039642:Eukaryotic Initiation Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C067777:Sxl protein, Drosophila; D014157:Transcription Factors; C094166:msl-2 protein, Drosophila