Unraveling novel roles of the cellular decapping activators Lsm1-7 and Dhh1 in translation control through viral studies
Translation control is a vital aspect of gene expression for both viruses and their cellular hosts. We have previously shown that the cellular mRNA decay activators Dhh1 and Lsm1-7 promote translation of positive-strand RNA [(+)RNA] viral genomes and their subsequent transport from the cellular tran...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/288313 |
| Acceso en línea: | http://hdl.handle.net/10803/288313 |
| Access Level: | acceso abierto |
| Palabra clave: | Positive strand RNA virus Tranlation regulation Deccaping activators DEAD-box helicase Host factors Virus ARN de cadena positiva Regulación de traducción Activadores del decapping Factor celular 578 |
| Sumario: | Translation control is a vital aspect of gene expression for both viruses and their cellular hosts. We have previously shown that the cellular mRNA decay activators Dhh1 and Lsm1-7 promote translation of positive-strand RNA [(+)RNA] viral genomes and their subsequent transport from the cellular translation machinery to replication complexes, a process that requires translation repression. These key steps in the replication of all (+)RNA viruses require profound rearrangements of the viral ribonucleoprotein (RNP) composition. How cellular decapping activators promote translation and replication of viral genomes remains unknown. Using the replication of the Brome mosaic virus in yeast, a fruitful model system for (+)RNA viral replication, we show that Dhh1 and Lsm1-7 function differentially in viral RNA translation and replication by assembling alternative mRNP complexes. The dependence on Dhh1 for viral RNA translation initiation is mediated by specific cis-acting sequences in the viral UTRs and a stem-loop in the ORF. Excitingly, by ribosome profiling analyses we identify a specific subset of cellular mRNAs that also depends on Dhh1 for translation. These mRNAs have as (+)RNA genomes long 5´UTR and highly structured 5´UTRs and ORFs. Moreover, they are enriched in mRNAs related to ribosome biogenesis. Interestingly, ribosome biogenesis is often altered in cancer cells and we and others determine that DDX6, the human ortholog of Dhh1, is indeed overexpressed in pancreatic and colon cancer. In conclusion, our results demonstrate that components of the cellular decapping machinery have a broad function in translational regulation. This enables fast fine-tuning of gene expression in response to perturbations. |
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