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Mécanismes de maintenance de l'intégrité de l'ADN mitochondrial humain suite à des cassures double-brin

Abstract : Mitochondria are organelles that possess their own genome, the mitochondrial DNA (mtDNA). Repair of oxidative damages, defective replication, or various exogenous sources, such as chemotherapeutic agents or ionizing radiations, can generate double-strand breaks (DSBs) in mtDNA. MtDNA encodes for essential proteins involved in ATP production and maintenance of integrity of this genome is thus of crucial importance. Mutations in mtDNA are indeed found in numerous pathologies such as mitochondrial myopathies, neurodegenerative disorders or cancers. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown.To elucidate this question, we have generated mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSBs repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content, followed by reamplification of intact mtDNA molecules. We have demonstrated that none of the known mitochondrial nucleases are involved in mtDNA degradation and that DNA loss is not due to autophagy, mitophagy or apoptosis but to a selective mechanism. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs. Global approaches are ongoing to identify proteins involved in degradation of damaged mtDNA following DSBs, mainly an RNAi screen targeting 80 nucleases. In parallel we are interested in a family of phosphohydrolases named Nudix and their putative protective role in sanitizing the nucleotides pool in mitochondria.
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https://tel.archives-ouvertes.fr/tel-01729121
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Submitted on : Monday, March 12, 2018 - 1:15:08 PM
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2017CLFAC047_MORETTON.pdf
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  • HAL Id : tel-01729121, version 1

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Amandine Moretton. Mécanismes de maintenance de l'intégrité de l'ADN mitochondrial humain suite à des cassures double-brin. Génétique humaine. Université Clermont Auvergne, 2017. Français. ⟨NNT : 2017CLFAC047⟩. ⟨tel-01729121⟩

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