Systematic functional analyses of spliceosomal components reveal novel mechanisme of alternative splicing regulation
Alternative splicing is an essential regulatory layer of gene expression that expands the coding potential of the genome in multicellular organisms. The spliceosome -the sophisticated machinery involved in intron removal- allows versatile regulation of gene expression programs. The splicing process...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/385718 |
| Acceso en línea: | http://hdl.handle.net/10803/385718 |
| Access Level: | acceso abierto |
| Palabra clave: | Alternative splicing Anti-tumor drugs Fas/CD95 Pre-mRNA splicing Spliceosome Regulatory networks RNA binding SR proteins Zinc Finger Empalmament alternatiu Medicaments antitumorals RNA missatger Espliceosoma Dit de zinc Procesamiento alternativo 575 |
| Sumario: | Alternative splicing is an essential regulatory layer of gene expression that expands the coding potential of the genome in multicellular organisms. The spliceosome -the sophisticated machinery involved in intron removal- allows versatile regulation of gene expression programs. The splicing process relies on the dynamic interplay between hundreds of components of the spliceosome, and the steps at which the complex process of the splicing reaction can be regulated remain largely unknown. The main objective of this thesis has been to develop high- throughput approaches to systematically identify novel regulators of alternative splicing, as well as to study the mechanisms by which they modulate splice site choice. We have identified a variety of regulators of Fas/CD95 alternative splicing within and outside of the splicing machinery and provide novel insights into connections between iron homeostasis and alternative splicing regulation. Using computational networks, we carried out a systematic functional analysis of the spliceosome components and their regulatory potential. Our results reveal the extensive regulatory plasticity of core spliceosome components throughout its assembly process. They also identified links between alternative splicing and iron homeostasis, providing a mechanism by which iron modulates alternative splicing through regulation of the RNA binding properties of a Zinc knuckle domain in the SR regulatory protein SRSF7. The results of this thesis highlight the value of high throughput technologies and network analyses to study complex molecular mechanisms, and unveils novel functional connections between the splicing machinery and other cellular processes. |
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