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Cretaio, Erica (2008) DNA Topoisomerasi IB umana: studi sul meccanismo catalitico e sulla farmaco-resistenza. [Tesi di dottorato]

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Abstract (inglese)

Eukaryotic DNA topoisomerase I (Top1p) catalyzes changes in DNA topology via the formation of a covalent enzyme-DNA intermediate, which is reversibly stabilized by the anticancer agent camptothecin (CPT). Crystallographic studies of the 70-kDa C terminus of human Top1p bound to duplex DNA describe a monomeric protein clamp circumscribing the DNA helix. The structures, which lack the N-terminal domain, comprise the conserved clamp, an extended linker domain, and the conserved Cterminal active site Tyr domain. CPT bound to the covalent Top1p-DNA complex limits linker flexibility, allowing structural determination of this domain. We previously reported that mutation of Ala653 to Pro in the linker increases the rate of enzyme-catalyzed DNA religation, thereby rendering Top1A653Pp resistant to CPT (Fiorani, et al., 2003;). Molecular dynamics studies suggested mutation-induced increases in linker flexibility alter Top1p catalyzed DNA religation. However, despite a wealth of biochemical, structural and modeling data on Top1p structure and activity, there is little direct evidence of linker domain flexibility influencing the geometry of the active site. To address this question we asked if the enhanced rate of DNA religation, imparted by the A653P linker mutation, would suppress the DNA religation defect induced by the T718A active site mutation. Indeed, here we describe that the combination of the two mutations (in Top1A653P/T718A), abolished the lethal phenotype of yeast cells expressing the single T718A mutant. The double mutant enzyme was catalytically active in vitro and in vivo, yet was resistant to CPT. Taken together these data indicate long range communications between the flexible linker domain and the active site of the enzyme. The specific activity of the double mutant was decreased in vivo and in vitro, consistent with a decrease in DNA binding. These findings support a model where changes in the flexibility or orientation of the linker alter the geometry of the active site and thereby the kinetics of DNA cleavage/religation catalyzed by Top1p. The X-ray crystal structure of the enzyme covalently joined to DNA and bound to the CPT analog Topotecan suggests that there are two classes of mutations that can produce a CPT-resistant enzyme. The first class includes changes in residues that directly interact with the drug, whereas a second class alters interactions with the DNA and thereby destabilizes the drug binding site. The Thr729Ala, that is part of a hydrophobic pocket in the enzyme C-terminal domain, belongs to a third group of mutations that confer CPT resistance, but do not interact directly with the drug or the DNA. The Thr729Ala mutation has been firstly identified to impart drug resistance on human topoisomerase I in the CPT-11 (Irinotecan, a CPT analog) resistant human lung cancer cell line, PC-7/CPT (Kubota et al., 1992) but our data reveal that the equivalent effect with CPT can not be observed if the enzyme, harboring the same mutation, is expressed in the yeast Saccaromyces cerevisiae. Interestingly, looking at the protein structure, Thr729 seems to be too distant to contact the drug directly and it is not clear how the structure or stability of the intercalation drug-binding pocket is affected by the mutation. The Thr729 resides in the hydrophobic core of the Cterminal domain 12.4 Å from the catalytic tyrosine and 13.1 Å from Asn722 that establishes a water-mediated contact directly to the drug. Changing the Asn722 to Ser, shortening the side chain, is sufficient to impart CPT resistance to the protein (Fertala et al., 2000). According to these data, Redinbo and co-authors assumed that the basis of the Thr729 mutants CPT resistance come from the destabilization of the C-terminal region that could lead to the specific shift in position of Asn722, consequentially inducing the breakage of the water-mediated contact with the drug (Chrencik, et al., 2004). In order to confirm these hypotheses, we analyzed the effect of Thr729 substitutions to Lys, Pro and Glu on the in vivo and in vitro catalytic activity and drug sensitivity of the human DNA topoisomerase I. These three substitutions were chosen for their positive or negative charge, Lys and Glu, respectively, and for their capability in distorting the a-helix as in the case of Pro. Our results show that the 729 position is a key point in maintaining the correct geometry of the hydrophobic pocket of the C-terminal domain. In fact, even if the enzyme keeps on its catalytic properties and its sensitivity to CPT in the presence of a Thr729Ala mutation, a dramatic CPT resistance effect could be observed when the Thr729 was mutated to Lys or Glu, and a minor consequence could be seen in the presence of a Pro. Furthermore, the Thr729Glu mutant shows a remarkable defect in the DNA binding indicating that the integrity of the C-terminal geometry is essential for the preservation of the correct interactions between the enzyme and its substrate during the progression of the catalytic cycle. Dynamic simulation experiments propose a structural and dynamical interpretation for the role played by residue 729 in these long-range protein–DNA communications (Chillemi et al. 2008 ). The Thr729 is located in the C-terminal domain and its side chain forms a 2.6-A? hydrogen bond with the hydroxyl group of Tyr619. This interaction stabilizes the contacts between the Cterminal and core subdomain III regions of the CAT, that extends from the top half of the molecule downward by a couple of long helices (8 and 9) functioning as an hinge that opens and closes the enzyme around DNA. The most complete structured Nterminal domain of the topoisomerase I protein runs from residue Ile215 to Gly201. These fifteen amino acids pack against part of core subdomain I, the C-terminal domain, and the putative hinge region of the core subdomain to form a hydrophobic cluster. Notably, the cluster is well conserved among eukaryotic type IB topoisomerases (Redinbo et al., 2000). This stretch of N-terminal domain interacts with the ?-helix that connects the two lobes of the protein; specifically, the Trp205 is closer to Arg434, located at the top of “connecting” helix. Rising from these observations, the N-terminal domain positioning is thought to play an important role in the upper portion of this helix that is considered as an hinge involved in the opening and clamping crucial movement in the topoisomerase catalytic process; this portion is also protease sensitive only in the absence of the DNA (Stewart et al., 1996). The residue Pro431 is located in the upper portion of hinge region; where is situated a bent loop . The presence of this structure could be caused by this residue. In order to verify the function of proline 431 we realized a Pro431Gly mutant, introducing a residue lacking of side chain. In this way is possible remove the structural constrictions imposed by proline residue. To clarify the role of interactions between Nterminal domain and hinge region we have been realized all mutants in full length and Topo70 versions. To investigate the cluster of interactions between Arg 434 and Trp 205 the residue Arg 434 is mutated in Ala and Cys. These two substitutions were chosen for their capability in modifying the charge and structure of region in the Ala case and for capability in making a covalent bound in the double mutant (W205CR434C) in the case of Cys. The hinge mutant are lethal when express in yeast system. The lethality is not influenced by presence of N-terminal domain , in fact the topo70- mutants is enable to grow in GAL presence. All mutants present a reduction in specific activity but this defect in catalysis is not associated with reduction in substrate affinity. In time course experiments, performed in presence of DNA excess, the mutants present a more distributive mode of action. In the case of 434 mutants this loss of activity is associated with shift of cleavage/relegation equilibrium toward cleavage as confirmed also by cleavage assay. The mutants P431G present defect in relaxation caused by alteration in the control of strand rotation. Both with the Top1P431Gp and Top1P431G-70p mutant, a low, but reproducible level of DNA cleavage was observed in the absence of CPT . For the first the products of reaction are located in upper part of gel and corresponding to DNA substrates greater than 100 nucleotides in length. In the case of Top1P431G-70p mutant the products are placed in the lower part of gel and related to short DNA fragments. These results support a presence of interaction between N-terminal domain and hinge region. These results support a presence of interaction between N-terminal domain and hinge region. The N-terminal domain controls the substrate specificity, modulating the type and quality of protein-DNA interaction.

Abstract (italiano)

La DNA topoisomerasi I (Top1p) catalizza cambiamenti nella topologia del DNA mediante la formazione di un intermedio covalente enzima-DNA, che è reversibilmente stabilizzato dall’ agente antitumorale camptotecina (CPT).Studi cristallografici di una Top1p, mancante della porzione N-terminale, legata covalentemente ad un filamento di DNA, mostrano una proteina monomerica che lega il substrato come una tenaglia. In questa struttura sono individuabili un dominio core, che costituisce insieme al domino C-terminale la parte globulare della proteina e un dominio linker. La CPT lega l’ intermedio covalente limitando la flessibilità del dominio linker e consentendone la cristallizzazione. Precedentemente abbiamo dimostrato che la mutazione del residuo Ala653 in Pro determina un incremento nella tasso di riligazione rendendo il mutante Top1A653Pp resistente alla CPT (Fiorani, et al., 2003).Studi di dinamica molecolare suggeriscono che questa mutazione si associa ad un incremento nella flessibilità del dominio linker capace di alterare l’ equilibrio della reazione catalizzato dalla Top1p. Tuttavia i dati derivanti da studi strutturali, biochimici e di dinamica molecolare, condotti su questa proteina, forniscono scarse evidenze sul fatto che la flessibilità del dominio linker possa influenzare la geometria del sito attivo. Per verificare se l’ incremento nel tasso di riligazione causato dalla mutazione A653P, potesse sopprimere il difetto nella riligazione indotto dalla mutazione T718A, localizzata nel sito attivo, abbiamo realizzato un doppio mutante Top1 A652P-T718Ap (DM).Il doppio mutante è vitale, cataliticamente attivo sia in vivo che in vitro e resistente alla CPT. Questi risultati suggeriscono l’esistenza di interazioni a lungo raggio tra il dominio linker ed il sito attivo. L’ attività specifica del doppio mutante, sia in vivo che in vitro, dimostra la presenza di una riduzione dell’ affinità per il DNA, supportando l’ipotesi secondo cui alterazioni nella flessibilità o nell’orientamento di questo dominio influenzino profondamente la geometria del sito catalitico, modificando la cinetica del taglio e della riligazione catalizzata dalla Top1p. La struttura cristallografica del complesso ternario, realizzata in presenza dell’ analogo della CPT topotecano (TPT), suggerisce la presenza di due classi di mutazioni capaci di indurre resistenza all’ azione dell’ inibitore. La prima classe include i cambiamenti nei residui che interagiscono direttamente con il farmaco, mentre la seconda comprende i residui che, se mutati, determinano un alterazione nelle interazione stabilite con il DNA e la tasca di legame della CPT. La mutazione Thr729Ala si trova entro un cluster idrofobico situato nel dominio Cterminale e come tale, appartiene ad una terza classe di mutazioni capaci di conferire resistenza alla CPT senza interagire direttamente con il farmaco o il DNA. La mutazione Thr729Ala è stata identificata per la prima volta in linee cellulari tumorali PC-7/CPT resistenti al CPT-11( ironotecano un analogo della CPT) (Kubota et al., 1992). Tuttavia, i nostri dati rivelano che gli stessi effetti non sono evidenziabili se l’ enzima viene espresso nel lievito Saccaromyces cerevisiae. Se si osserva la struttura proteica il residuo Thr729 è distante dal sito di legame del farmaco per cui non è chiaro come una sua mutazione possa modificare la dinamica dell’ interazione tra CPT e complesso binario. La Thr729 si trova nel dominio C-terminale a 12.4 Å dalla tirosina catalitica e 13,1Å dal residuo Asn722 che stabilisce un legame mediato dall’ acqua con la CPT. La mutazione Asn722Ser, che determina un accorciamento della catena laterale, induce una condizione di resistenza (Fertala et al., 2000). Redinbo e coautori hanno ipotizzato che le basi della resistenza alla CPT, causata da mutazioni del residuo 729, siano dovute ad uno spostamento del residuo Asn722 con conseguente soppressione del legame con le CPTs (Chrencik, et al., 2004). per confermare questa ipotesi abbiamo analizzato il comportamento di altre tre sostituzioni: Lys, Pro e Glu. Queste sostituzioni sono state scelte per la loro carica positiva o negativa, nel caso della Lys e del Glu, e per la capacità di distorcere l’?-elica nel caso della Pro. I risultati dimostrano che il residuo Thr729 svolge un ruolo chiave nel mantenimento della corretta geometria della tasca idrofobica collocata nella regione C-terminale. Infatti, la mutazione Thr729Ala produce un’ enzima che presenta un attività in vivo, in vitro e una sensibilità alla CPT del tutto paragonabili all’ enzima WT. Quando la Thr729 è mutata in Lys o Glu si evidenzia una condizione di resistenza alla CPT ,che si traduce in una sensibilità alterata nel caso della mutazione Thr729Pro. Inoltre, il mutante Thr729Glu evidenzia forti difetti nell’ interazione con il substrato suggerendo che il mantenimento della corretta geometria della regione C-terminale è necessario per preservare le interazioni tra l’enzima ed il DNA durante la progressione del ciclo catalitico. Gli esperimenti di dinamica molecolare forniscono un‘interpretazione strutturale e dinamica del ruolo svolto dalla Thr729 nelle interazioni a lungo raggio presenti tra proteina e DNA (Chillemi et al. 2008). La catena laterale della Thr729 forma un legame idrogeno con il gruppo idrossilico della Tyr619, stabilizzando i contatti tra dominio C-terminale e la regione del subdominio III. La struttura più completa della Top1 contiene una porzione dell’ N-terminale che va dal residuo Ile 215 alla Gly201. Questi quindici aminoacidi sono impaccati vicino al subdominio I, al dominio C-terminale e alla regione hinge ove costituiscono un cluster idrofobico conservato in tutte le topo isomerasi IB eucaristiche (Redinbo et al., 2000). Questa porzione del dominio N-terminale interagisce con l’?-elica del perno ed, in particolare, il Trp 205 è vicino all’ Arg434, situata all’ inizio dell’ elica hinge. All’apice dell’hinge è presente un loop piegato contenete la Pro431. Per verificare se tale caratteristica strutturale è causata dalla presenza della prolina abbiamo mutato questo residuo in glicina, un aminoacido privo di catena laterale. In questo modo è possibile valutare se il ripiegamento del loop è causato dalla prolina e se tale conformazione possiede un significato funzionale. Per chiarire il ruolo delle interazioni presenti tra questa regione e la porzione N-terminale della proteina tutti i mutanti sono stati realizzati nella forma full lenght e Topo70. Inoltre il residuo Arg434 è stato mutato in Ala e Cys. La prima sostituzione è stata scelta per la sua capacità di alterare l’ intorno chimico sia strutturalmente che elettrostaticamente , la seconda per la capacità di formare un ponte disolfuro nel doppio mutante W205C-R434C, in cui la regione perno è ancorata covalentemente al domini N-terminale. Tutti i mutanti risultano letali quando espressi in lievito, la loro letalità non è dipendente dalla presenza del dominio N-terminale, poiché anche i mutanti Topo70 sono incapaci di formare colonie in condizioni di espressione. Tutte le proteine presentano una riduzione nell’ attività specifica, che tuttavia, non è associata ad un calo nell’ affinità per il substrato. Nelle cinetiche di rilassamento in eccesso di DNA, i mutanti presentano un comportamento distributivo. Nel caso dei mutanti del residuo 434 questa perdita di attività è associata ad uno spostamento dell’ equilibrio di reazione verso il taglio, come confermato dai saggi di taglio. I mutanti Top1P431Gp e Top1P431G70-p presentano difetti nel rilassamento del DNA probabilmente imputabili ad alterazioni nel controllo della rotazione del filamento a valle del sito di taglio. Nei saggi di taglio per entrambi è presente un basso ma riproducibile accumulo di complessi in assenza dell’ inibitore. Per il mutante Top1P431Gp i prodotti della reazione sono localizzati nella parte superiore del gel e corrispondenti a frammenti di DNA più lunghi di 100 coppie di basi. Nel caso del mutante Top1P431G70-p i prodotti di reazioni sono posizionati nella metà inferiore del gel e quindi equivalenti a frammenti di DNA corti. Questi risultati confermano la presenza di interazioni tra dominio N-terminale e regione hinge; inoltre suggeriscono che la regione N-terminale controlli la specificità del riconoscimento modulando la qualità e il tipo d’interazione tra enzima e DNA.

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Tipo di EPrint:Tesi di dottorato
Relatore:Benedetti, Piero
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOCHIMICA E BIOTECNOLOGIE > BIOTECNOLOGIE
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:2008
Parole chiave (italiano / inglese):DNA topoisomerasi IB umana, Camptotecina (CPT), topologia, farmaco-resistenza
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1712
Depositato il:29 Gen 2009
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