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Leanza, Luigi (2009) Origine e regolazione del pool mitocondriale dei deossinucleotidi guaninici. [Tesi di dottorato]

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Abstract (inglese)

Nuclear and mitochondrial DNA replication require a Corrected balance of dNTP. Mutations affecting mitochondrial DNA or factors involved in its replication or maintenance lead to the onset of mitochondrial diseases. The molecular output of these diseases are dysfunctions in the respiratory chain activity with consequent effects on mitochondrial energy production. For these reasons, tissues with high energy requirement, such as liver, brain and muscles, are specifically or preferantially affected.
Mitochondrial DNA depletion syndromes (MDS) are one group of diseases characterized by reduction of mtDNA copy number and caused by mutations in nuclear genes. Four of such genes are involved in dNTP synthesis: thymidine phosphorylase (TP), mitochondrial thymidine kinase 2 (TK2), deoxyguanosine kinase (dGK) and the p53 dependent isoform of the small subunit of ribonucleotide reductase (p53R2). Mutated thymidine kinase 2 and deoxyguanosine kinase lead to the myopathic and hepatocerebral form of mitochondrial DNA depletion syndromes, which are severe diseases with an early onset resulting in death during the first year of life.
Deoxyguanosine kinase is an enzyme involved in the mitochondrial salvage pathway for dNTP synthesis. It phosphorylates deoxyguanosine, deoxyinosine, deoxyadenosine and deoxycytidine, and a number of different deoxynucleoside analogs. Deoxyguanosine kinase is coded by the gene DGUOK, localized in the nuclear genome, and it is constituted by an omodimer of two identical monomers of 28 kDa each.
dGTP pool metabolism is more complex. Deoxyguanosine, dGTP precursor, can be phosphorylated both by deoxycytidine kinase and by deoxyguanosine kinase. Moreover in the cytosol it can also be degraded by the purine nucleoside phosphorylase to guanine and deoxyribose-1-phosphate and then the base can be recycled by hypoxantine-guanine-phosphorybosiltransferase in the ribonucleotide pool and RNA.Results have shown that cytosolic and mitochondrial dGTP pools can communicate and exchange deoxynucleotides, even if they are separated by the mitochondrial membrane. We have observed both movement of guanine deoxynucleotides from the mitochondria to the cytosol and from the cytosol to mitochondria. In this way a dynamic equilibrium arise between the two pools, determined by the synthesis of dGTP and its incorporation into DNA and degradation.
Most of the dGTP necessary in cycling and quiescent cells is produced by ribonucleotide reductase activity. The dGTP pool has a rapid turnover, shown by the complete and fast loss of radioactivity from the pools when the isotope was removed from the medium.
When we inhibited DNA synthesis by aphidicolin we observed no pool changes, possibly due to an increased degradation of dGTP. Instead blocking ribonucleotide reductase with hydroxyurea, we decreased dGTP turnover leading to radioactivity accumulation in the cytosolic deoxynucleotide pool.
All these observations are in agreement with those obtained for the dTTP pools, suggesting that the inferred rules for dNTP synthesis and regulation can be extended also to the other deoxynucleotide pools.

Abstract (italiano)

Il corretto bilanciamento del pool dei deossinucleotidi è importante per la replicazione del DNA nucleare e di quello mitocondriale.
Mutazioni a carico del DNA del mitocondrio o di fattori necessari alla sua replicazione ed alla sua stabilità provocano l’insorgenza di patologie mitocondriali. Il fenotipo dal punto di vista molecolare è una disfunzione della catena respiratoria, con una ridotta produzione di energia da parte del mitocondrio. Per queste ragioni, i fenotipi clinici osservati nei pazienti affetti da queste patologie coinvolgono organi e tessuti ad alta richiesta energetica, come il fegato, il cervello, e i muscoli scheletrici.
Una classe di queste patologie è quella delle sindromi da deplezione del DNA mitocondriale (MDS), nella cui patogenesi sono coinvolte anche mutazioni a carico di geni responsabili della sintesi dei dNTP all’interno della cellula. Tra questi vi sono i geni per la timidina fosforilasi (TP), la timidina chinasi 2 mitocondriale (TK2), la deossiguanosina chinasi (dGK) e un’isoforma della subunità minore della ribonucleotide reduttasi p53 dipendente (p53R2).La deossiguanosina chinasi è uno delle due deossinucleoside chinasi della via mitocondriale di recupero dei dNTP. In particolare, essa fosforila la deossiguanosina, la deossiinosina, la deossiadenosina, e la deossicitidina, oltre a diversi analoghi nucleosidici. La deossiguanosina chinasi è codificata dal gene DGUOK, localizzato nel genoma nucleare, ed è un omodimero costituito da due monomeri di 28 kDa ciascuno.
Finora lo studio sul metabolismo dei deossinucleotidi si era concentrato principalmente sul pool del dTTP, il quale è più facile da analizzare visto che il suo precursore timidina viene utilizzato solamente all’interno dle pool dei deossinucleotidi, dalla timidina chinasi 1 nel citosol e dalla timidina chinasi 2 nel mitocondrio. Lo studio del pool del dGTP, invece, è più complesso in quanto il suo precursore, la deossiguanosina, può essere fosforilata nel citosol dalla deossicitidina chinasi, e nel mitocondrio dalla deossiguanosina chinasi, ma può anche essere velocemente degradata a guanina nel citosol, dalla fosforilasi dei nucleosidi purinici. La base viene poi riciclata dall’enzima ipoxantina-guanina-fosforibosiltransferasi ed incorporata nel pool dei ribonucleotidi e nell’RNA. Per poter seguire l’incorporazione della deossiguanosina nel dGTP attraverso la sola via di recupero abbiamo dovuto inibire con l’Immucillina H la degradazione citosolica da parte della fosforilasi dei nucleosidi purinici, ed utilizzare cellule mutanti nell’enzima ipoxantina-guanina-fosforibosiltransferasi, così da evitare il riciclo della guanina nel pool dei ribonucleotidi. Solamente in queste condizioni è stato possibile seguire l’incorporazione del precursore nei pool del dGTP e quindi nel DNA.
il pool citosolico e mitocondriale del dGTP comunicano e si scambiano nucleotidi. É stato osservato un movimento bidirezionale di deossinucleotidi dal mitocondrio verso il citosol, e viceversa. Questo scambio favorisce l’instaurarsi di un equilibrio dinamico tra i due compartimenti, determinato dalla continua sintesi di dGTP e dalla incorporazione nel DNA oppure dalla sua degradazione ed eliminazione. In esperimenti di pulse e chase abbiamo osservato che il pool del dGTP ha un turnover molto rapido che comporta una completa perdita in pochi minuti della radioattività incorporata nel pool citosolico e mitocondriale.Abbiamo anche valutato gli effetti dell’inibizione della sintesi del DNA nucleare attraverso l’aggiunta di afidicolina e dell’inibizione della sintesi de novo tramite trattamento con l’idrossiurea, inibitore specifico della ribonucleotide reduttasi. Gli esperimenti con afidicolina hanno dimostrato che nonostante il dGTP non venga incorporato nel DNA esso non si accumula nel pool ma viene degradato ed eliminato velocemente. Nel caso invece dell’idrossiurea, l’inibizione della ribonucleotide reduttasi provoca un accumulo di radioattività nei deossinucleotidi della guanina nel citosol dovuta ad una riduzione del turnover del dGTP.
Le informazioni sugli scambi tra citosol e mitocondri e sull’importanza della sintesi de novo per il rifornimento dei dNTP mitocondriali ricavte da questi esperimenti con la deossiguanosina sono in accordo con quelle raccolte in precedenza per il pool del dTTP, così da poter concludere che esse rappresentano leggi generali che regolano la sintesi e regolazione dei pool dei dNTP e sono valide per tutti e quattro i deossinucleotidi.

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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 > NEUROBIOLOGIA
Data di deposito della tesi:02 Febbraio 2009
Anno di Pubblicazione:Gennaio 2009
Parole chiave (italiano / inglese):Mitocondrio, dGTP, Deossiguanosina, Chinasi, Analoghi nucleotidici, Malattie mitocondriali
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/06 Anatomia comparata e citologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1913
Depositato il:02 Feb 2009
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