The Role of EXD2 in the maintenance of mithocondrial homeostasis
Mitochondrial dysfunction arising from aberrant mitochondrial nucleic acid homeostasis has been associated with various pathologies. In this thesis, we aim to characterize a putative mitochondrial exonuclease, EXD2, and the consequences of its loss in cell metabolism. For that purpose we use three a...
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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:10803/328716 |
| Acceso en línea: | http://hdl.handle.net/10803/328716 |
| Access Level: | acceso abierto |
| Palabra clave: | EXD2 WRN HIF-1α exonuclease exoribonuclease DNA RNA tRNA sRNA mithocondria metabolism aging DNA repair mithocondrial replication breast cancer hypoxia Exonucleasa Exoribonucleasa Mitocondria Metabolismo Envejecimiento Reparación del ADN Replicación mitocondrial Cancer de mama Hipoxia 577 |
| Sumario: | Mitochondrial dysfunction arising from aberrant mitochondrial nucleic acid homeostasis has been associated with various pathologies. In this thesis, we aim to characterize a putative mitochondrial exonuclease, EXD2, and the consequences of its loss in cell metabolism. For that purpose we use three approaches: 1) Biochemical assays with bacterially purified EXD2 to study its enzymatic activity, 2) In vitro experiments with cell lines to study the phenotype of cells with altered EXD2-levels, and, 3) In vivo experiments with a mouse xenograft model and D.melanogaster to study the consequences of EXD2-loss in tumors and at the organismal level. Our work shows, that EXD2 is a uniquely versatile mammalian exonuclease able to bind and degrade various DNA and RNA substrates. We demonstrate that loss of EXD2 in cancer cells leads to alterations in mtDNA, various metabolic changes and aberrant hypoxia signaling. We also describe how, in vivo, this leads to inhibition of breast tumor growth and increased lifespan in fruitflies. Taken together, our observations provide a link between mitochondrial nucleic acid maintenance and large-scale metabolic alterations influencing tumor growth and aging. |
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