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Franzolin, Elisa (2009) Modelli cellulari di deficienze per la timidina chinasi mitocondriale. [Tesi di dottorato]

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Abstract (inglese)

MtDNA replication is not limited to the S phase of the cell cycle but takes place also in differentiated cells where nuclear DNA replication has stopped. The cell needs a balanced supply of the four deoxyribonucleoside triphosphates (dNTP) to replicate and repair its DNA properly. Eukaryotic cells contain two separate pools of dNTPs, a cytosolic-nuclear pool and a mitochondrial pool which are synthesized through two pathways: the cytosolic de novo synthesis and the two salvage pathways. In proliferating cultured cells the canonical cytosolic ribonucleotide reductase (RNR) is the prominent synthetic enzyme that by de novo synthesis provides most of dTTP. Otherwise dTTP can be synthesized by phosphorylation of thymidine to dTMP via the mitochondrial and the cytosolic salvage pathway catalyzed respectively by TK2 and the cytosolic thymidine kinase (TK1). The aim of this work is to clarify the mechanisms involved in dTTP pool metabolism in human cells, focusing on the role of TK2 in quiescent cells. We also investigate the mitochondrial carrier responsible for the exchange of pyrimidine precursors exchange between cytosol and mitochondria.

Abstract (italiano)

La replicazione del mtDNA non è limitata alla sola fase S come quella del DNA nucleare, ma avviene per tutta la durata del ciclo cellulare nelle cellule proliferanti e anche nelle cellule quiescenti e differenziate. Perché la sintesi e la riparazione del DNA si svolgano con precisione le cellule devono disporre di dNTP in quantità adeguate e proporzioni corrette. Nelle cellule eucariotiche esistono due pool di dNTP separati ma comunicanti, uno citoplasmatico ed uno mitocondriale e il loro mantenimento avviene attraverso due vie: la sintesi de novo citoplasmatica e le sintesi di recupero citosolica e mitocondriale. Nelle cellule proliferanti il dTTP è sintetizzato sia attraverso la sintesi de novo il cui enzima chiave è la ribonucleotide reduttasi (RNR), sia attraverso le vie citosolica e mitocondriale di recupero dei deossiribonucleosidi, dove la timidina viene fosforilata a dTMP rispettivamente dalla timidina chinasi citosolica (TK1) e dalla TK2. Lo scopo di questo lavoro di dottorato è chiarire i meccanismi coinvolti nel metabolismo del pool del dTTP in cellule umane, ponendo particolare attenzione all’attività enzimatica della TK2 in cellule quiescenti, dove la TK1 non è attiva e all’identificazione del trasportatore responsabile dello scambio dei precursori pirimidinici tra citosol e mitocondri.

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Tipo di EPrint:Tesi di dottorato
Relatore:Bianchi, Vera
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):DNA mitocondriale, timidina chinasi mitocondriale, deossiribonucleotidi
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/06 Anatomia comparata e citologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1697
Depositato il:29 Gen 2009
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