Molecular mechanisms of msl2 mRNA translational regulation
Regulation of msl2 translation is a key step in the modulation of X-chromosome dosage compensation. MSL2 is the limiting subunit of the dosage compensation complex, an assembly that promotes hyper-transcription of the single male X-chromosome to equalize expression of X-linked genes between males an...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/663873 |
| Acceso en línea: | http://hdl.handle.net/10803/663873 |
| Access Level: | acceso abierto |
| Palabra clave: | Translation Msl2 Sex-lethal EIF3d Cap-independent translation Traducción Traducción cap-indepeneiente 577 |
| Sumario: | Regulation of msl2 translation is a key step in the modulation of X-chromosome dosage compensation. MSL2 is the limiting subunit of the dosage compensation complex, an assembly that promotes hyper-transcription of the single male X-chromosome to equalize expression of X-linked genes between males and females. In females, dosage compensation must be repressed for viability, and this is achieved in large part by translational repression of msl2 mRNA. The female-specific protein Sex-lethal (SXL) binds to both untranslated regions (UTRs) of the msl2 transcript to inhibit two steps of translation initiation: SXL bound to the 3’ recruits the co-factor UNR and inhibits ribosomal recruitment; SXL bound to the 5’ UTR inhibits ribosomal scanning by promoting the recognition of an upstream AUG. In the lab, we recently found that eIF3d is a target of the 3’UTR repressor complex. In this thesis, we show that eIF3d can be recruited to the mRNA even in the absence of a cap structure by virtue of its binding to msl2 5’ UTR. Our results suggest that recruitment of this factor to the mRNA by multiple routes may sensitize translation of msl2 to inhibition of eIF3d. In addition, we have identified residues of SXL important for 5’ UTR, but not 3’ UTR, -mediated repression. Analysis of SXL variants with mutations in these residues has led us to identify two factors as likely mediators of inhibition via the 5’ UTR. Interestingly, the location of these factors in the ribosome allows us to propose an integrated model for translational repression that explains coordinated inhibition of ribosome recruitment and scanning by SXL. |
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