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Stevanoni, Martina (2017) The fine modulation of mammalian DNA replication in response to endogenous and exogenous stress conditions. [Ph.D. thesis]

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Abstract (italian or english)

DNA replication is essential to allow faithful inheritance of the genome. In mammalian cells, many replication origins are grouped within 200-400 kb regions called replication clusters, which are in turn enclosed in large replication domains (Méchali 2010; Cayrou et al. 2011). This hierarchical organisation is required for the temporal and spatial control of DNA replication and it allows modulating origin activation locally within clusters and globally at the level of replication domains (Yekezare et al. 2013).
During G1 several initiation sites are licensed, but only a subset is activated in the following S-phase (Ge et al. 2007; Blow & Ge 2009; Méchali 2010). Furthermore, origins fire stochastically within clusters and in different positions among cells in a population (Hyrien et al. 2003; Gilbert 2007; Méchali 2010). Remarkably, origin redundancy and plasticity are intrinsic features of the mammalian replication process necessary to face changes in chromatin organisation occurring during development and cell differentiation and to overcome replication stress (Cortez 2015; Alver et al. 2014; Palumbo et al. 2013; Zeman & Cimprich 2014). The temporal regulation of origin firing is established at the level of replication domains, which are conserved among subsequent cell cycles and classified as early, mid or late replicating according to their timing of activation throughout the S-phase (Hiratani et al. 2008; Pope & Gilbert 2013; Rivera-Mulia & Gilbert 2016b).
Replication profiles define the replication program in each cell type and are modulated according to the diverse developmental and differentiation cellular stages, as well as in response to replication stress (Palumbo et al. 2013; Courbet et al. 2008; Anglana et al. 2003). Replication profiles are determined by several parameters, including fork rates, origin choice and alternative replication patterns (i.e. unidirectional and asynchronous forks and pause/arrest events), and their regulation is implied by the flexible nature of the mammalian replication process. Hence, not only origin position but the whole replication dynamics must be taken into consideration to better elucidate the complex phenomena associated with mammalian DNA replication (Prioleau & MacAlpine 2016; Hyrien 2015; Palumbo et al. 2013). In this frame, single-molecule techniques represent the most appropriate tool to detect the intrinsic plasticity and cell-to-cell variability of mammalian genomes (Tuduri et al. 2010; Técher et al. 2016; Prioleau & MacAlpine 2016).
Here, I evaluated how replication profiles are regulated in response to endogenous and exogenous replication stress conditions. In particular, I considered the modulation of the mammalian replication program in relation to sequence organisation, cell growth and differentiation. For this purpose, different cellular models were used.
First, I focused on the effects of a trinucleotide repeat (TNR) expansion on DNA replication. TNR are among the most unstable genomic regions and variations of their length are implicated in many human neurodegenerative disorders (McMurray 2010; Lee & McMurray 2014). Expanded repeats are prone to form stable unusual DNA secondary structures (Mirkin & Mirkin 2007; Krasilnikova & Mirkin 2004), which are a well-known source of replication stress (Zeman & Cimprich 2014; Magdalou et al. 2014; León-Ortiz et al. 2014). A replication-based mechanism is largely accepted to be at the origin of expansion and instability of several TNR, including also the GAA-repeat expansion responsible for Friedreich’s ataxia (FRDA). To better understand this mechanism, different experimental systems from yeast to transfected or engineered human cells were employed (Follonier et al. 2013; Chandok et al. 2012; Kim et al. 2008), but none of them displayed the huge amount of repeats observed in patients’ cells. Thus, to understand how replication profiles are modulated in the presence of long repetitive sequences in the endogenous context, I used human lymphoblastoid cell lines derived from FRDA patients carrying an homozygous GAA-repeat expansion within intron 1 of the Frataxin (FXN) gene. In the presence of the GAA-repeat expansion an alteration of the replication timing was observed by interphase FISH and wide changes in the replication profiles were demonstrated. Indeed, in mutant cells, according to the frequency of duplicated FISH spots, the replication of the FXN gene was slowed or delayed during the first half of the S-phase. This effect was normalised in the latter part when both normal and expanded alleles complete their replication. Further, by molecular combing replication dynamics was monitored in a large genomic region harbouring FXN. By this approach I verified that the most relevant effect associated with the presence of the GAA-repeat expansion was the recruitment of additional dormant origins firing downstream the repeat, which can be considered as a rescue mechanism to assure replication of mutant alleles. As a consequence of dormant origin activation, a switch of the prevalent direction by which the expanded GAA-repeat is replicated was observed, indicating that the origin-switch model for TNR instability conform to the case of the GAA-repeat expansion, similarly to what observed at the FMR1 locus (Gerhardt et al. 2014). Same conclusions were reached in parallel in another study (Gerhardt et al. 2016). Remarkably, a strong reduction of unidirectional fork length was observed in mutant alleles with respect to the normal sequence and this may be considered as a second effect of the GAA-repeat expansion. In line with results obtained at the FMR1 locus (Gerhardt et al. 2014), in the present study recurrent paused/arrested forks were recorded in proximity of the short GAA-repeat in one of the normal cell lines analysed, suggesting a possible impact of the non-pathological GAA-repeat on fork progression. Interestingly, it was recently demonstrated an high occurrence of fork pausing at the expanded GAA-repeat in both undifferentiated and differentiated FRDA cells and these events were hypothesised to be caused by a collision between the replication and transcription machineries (Gerhardt et al. 2016). Understanding whether the origin-switch is the cause or instead a consequence of the GAA-repeat expansion will be necessary and future investigations will primarily contribute to clarify this aspect.
Secondly, I evaluated the effects of increased and unbalanced dNTP pools on the replication program. To ensure completion of DNA replication and to avoid genome instability, the balance among dNTP supply, degradation and consumption must be tightly controlled according to the rate of DNA synthesis (Rampazzo et al. 2010; Chabes & Stillman 2007; Chabosseau et al. 2011; Bester et al. 2011). Indeed, the limiting availability of nucleotide precursors has been widely demonstrated to induce replication stress by slowing fork progression and leading to activation of the DNA damage response (Anglana et al. 2003; Courbet et al. 2008). Conversely, the consequences of an increased supply of dNTPs were only partially depicted in yeast mutants, where replication forks move faster upon ribonucleotide reductase overexpression (Poli et al. 2012). Instead, the effects in mammalian cells are still unknown. Thus, here I used human primary fibroblasts and THP1 monocytes with increased and unbalanced dNTP pools due to depletion of SAMHD1, a protein involved in nucleotide metabolism (Franzolin et al. 2013; Miazzi et al. 2014). By this experimental models the replication profiles were analysed genome-wide by molecular combing in comparison to normal cells. My results indicated that independently of the dNTP pool imbalances, DNA replication proceeds mostly undisturbed in mutated and control fibroblasts, both in physiological and perturbed growth conditions. In contrast, an unexpected slow down of replication forks and a consequent increase in origin firing were detected in SAMHD1-depleted THP1 cells with respect to the wildtype cell line. This differential response to the high availability of nucleotide precursors may be ascribed either to a supposed cell type-specific activity of SAMHD1 or to the development of an adaptive phenotype in mutant fibroblasts compensating for the SAMHD1 depletion. Future goals will be to confirm these hypotheses and to evaluate the effects associated with fork stalling and restart.
Finally, I considered how replication dynamics are modulated during cell differentiation. It is well known that replication timing and replication profiles are cell type-specific and regulated according to changes in chromatin organisation occurring during development and cell differentiation (Palumbo et al. 2013; Hiratani et al. 2010; Hiratani et al. 2008). Hence, I assessed whether DNA replication is affected upon forced cell cycle reactivation. In particular, terminally differentiated mouse myotubes forced to re-enter the cell cycle were analysed by molecular combing in comparison to proliferating myoblasts. A significant reduction of fork rates was detected in reactivated myotubes with respect to proliferating muscle cells, resembling the effects seen under replication stress. This result is in line with previous evidence indicating that myotubes fail to complete their replication, as they are not able to properly expand their dNTP pools (Pajalunga et al. 2010; Pajalunga et al. 2017). Accordingly, after addition of nucleotide precursors the reduction of fork rate was partially ameliorated. However, the number of activated origins in each replication cluster was comparable between myotubes dosed with deoxynucleosides and myoblasts, suggesting that some regions along the genome are left under-replicated. Thus, the replication failure detected upon forced cell cycle re-entry may be ascribed not only to the depletion of nucleotide precursors, but also to the inability of these cells to recruit additional origins compensating for the reduction of fork speed. Interestingly, I found an increased proportion of unidirectional forks in reactivated myotubes when compared to myoblasts, in line with previous data obtained in human primary fibroblasts (Palumbo et al. 2013). Thus, unidirectional forks could be viewed as a remnant of the modality by which some replication domains are replicated when cells move toward terminal differentiation. In this perspective, understanding whether replication timing may be implicated in the replication impairment observed upon forced cell cycle reactivation remains an intriguing issue to be further unravelled.
The complexity of mammalian DNA replication may be ascribed to the intrinsic plasticity of the process, and drawing general conclusions from studies based on individual cellular models may be incautious. The results obtained in this study add new evidence for interpret this complexity, and offer insights for future investigations.

Abstract (a different language)

La replicazione del DNA è essenziale per consentire l’accurata trasmissione del materiale genetico durante le successive divisioni cellulari. Nelle cellule di mammifero i siti di inizio sono raggruppati in regioni genomiche di 200-400 kb, definite cluster replicativi, che sono a loro volta racchiusi in più ampi domini di replicazione (Méchali 2010; Cayrou et al. 2011). Questa organizzazione gerarchica consente di controllare il processo replicativo nello spazio e nel tempo tramite la regolazione dell’attivazione delle origini sia a livello locale all’interno dei cluster che a livello globale nei domini di replicazione (Yekezare et al. 2013).
Durante la fase G1 del ciclo cellulare le origini vengono “licenziate”, ma solo una parte di esse viene poi attivata nella successiva fase S (Ge et al. 2007; Blow & Ge 2009; Méchali 2010). Inoltre, le origini si attivano in modo stocastico all’interno dei cluster e sono diversamente distribuite nel genoma tra le diverse cellule (Hyrien et al. 2003; Gilbert 2007; Méchali 2010). Pertanto, le origini di replicazione nei mammiferi sono ridondanti e flessibili (Hyrien et al. 2003; Méchali 2010), caratteristiche indispensabili per fronteggiare non solo condizioni di stress replicativo, ma anche cambiamenti dell’organizzazione cromatinica quali quelli che avvengono durante lo sviluppo e il differenziamento cellulare (Cortez 2015; Alver et al. 2014; Palumbo et al. 2013; Zeman & Cimprich 2014). La regolazione temporale dell’attivazione delle origini è stabilita a livello dei domini replicativi, conservati in successivi cicli cellulari e classificati come regioni a replicazione precoce, intermedia e tardiva in base al loro timing di attivazione durante la fase S (Hiratani et al. 2008; Pope & Gilbert 2013; Rivera-Mulia & Gilbert 2016b).
I profili replicativi determinano il programma di replicazione specifico di ogni tipo cellulare e sono regolati durante le diverse fasi dello sviluppo e del differenziamento, così come in risposta a stress (Palumbo et al. 2013; Courbet et al. 2008; Anglana et al. 2003). I profili di replicazione sono definiti da vari parametri: oltre alla posizione e alla scelta delle origini, anche la velocità di progressione delle forche e i diversi pattern replicativi alternativi, quali forche unidirezionali, asincrone e in pausa, sono finemente regolati. Per la corretta interpretazione dei complessi fenomeni associati alla replicazione del DNA tutti questi pattern devono essere attentamente considerati (Prioleau & MacAlpine 2016; Hyrien 2015; Palumbo et al. 2013). Pertanto, per riuscire ad apprezzare la plasticità e la variabilità intrinseche del processo replicativo, le tecniche di analisi su singola molecola risultano essere particolarmente appropriate (Tuduri et al. 2010; Técher et al. 2016; Prioleau & MacAlpine 2016).
In questo lavoro ho valutato come vengono modulati i profili di replicazione in presenza di stress replicativi endogeni ed esogeni. In particolare, utilizzando diversi modelli cellulari ho analizzato come venga regolata la replicazione del DNA in regioni genomiche instabili, in particolari condizioni di crescita e durante il differenziamento.
In primo luogo, ho determinato gli effetti associati alla presenza di sequenze trinucleotidiche ripetute. Le triplette ripetute sono tra le regione del genoma più instabili e variazioni della loro lunghezza sono coinvolte in diverse malattie neurodegenerative (McMurray 2010; Lee & McMurray 2014). La loro caratteristica principale, strettamente collegata alla loro instabilità, è la capacità di formare strutture secondarie insolite (Mirkin & Mirkin 2007; Krasilnikova & Mirkin 2004), che inducono stress replicativo impedendo la normale progressione delle forche (Zeman & Cimprich 2014; Magdalou et al. 2014; León-Ortiz et al. 2014). Si pensa che tra i vari processi metabolici associati al DNA la replicazione abbia un ruolo fondamentale nel promuovere l’espansione e l’instabilità delle triplette ripetute, tra cui anche la ripetizione GAA associata all’atassia di Friedreich (Pearson et al. 2005; Cleary & Pearson 2005). Per capire meglio il meccanismo che sta alla base della loro instabilità sono stati utilizzati diversi modelli sperimentali, dal lievito a cellule umane ingegnerizzate (Follonier et al. 2013; Chandok et al. 2012; Kim et al. 2008). Tuttavia, rispetto ai lunghi tratti ripetuti osservati in cellule di pazienti, il limitato numero di triplette presente in questi modelli non consente uno studio approfondito degli effetti sulla sintesi del DNA. Per questo motivo, ho analizzato i profili replicativi in cellule linfoblastoidi umane derivate da pazienti affetti da atassia di Friedreich e che presentano in omozigosi un’espansione della tripletta GAA nel primo introne del gene Fratassina. In presenza dell’espansione ho osservato alterazioni del timing di replicazione del gene tramite la tecnica della FISH su nuclei in interfase, identificando vari cambiamenti nei profili replicativi della regione analizzata. Nello specifico, in base alla proporzione dei segnali di ibridazione duplicati ho potuto definire un ritardo nella replicazione del gene mutato durante la prima metà della fase S. Questo ritardo viene però recuperato nella parte finale della fase S, in quanto la replicazione del gene viene completata sia negli alleli normali che in quelli con tripletta espansa. Grazie alla tecnica del molecular combing ho poi monitorato le dinamiche di replicazione di una regione genomica di 850 kb contenente il gene Fratassina. Dalle mie analisi è emerso che l’effetto principale associato alla presenza della mutazione è l’attivazione di origini dormienti aggiuntive, situate a valle della tripletta ripetuta e all'interno del gene. Esse possono essere considerate come un meccanismo di recupero per assicurare il completamento della replicazione negli alleli mutati. In conseguenza dell’attivazione di queste origini dormienti, la direzione con cui la tripletta espansa viene replicata cambia, dimostrando che il modello di origin-switch, proposto per descrivere i meccanismi di instabilità delle triplette ripetute, è conforme al caso dell’espansione GAA nel gene Fratassina, come precedentemente osservato anche nel locus FMR1 (Gerhardt et al. 2014). In maniera indipendente un altro gruppo di ricerca è giunto alle mie stesse conclusioni (Gerhardt et al. 2016). Nel corso di queste analisi è emersa una significativa diminuzione della lunghezza delle forche unidirezionali negli alleli espansi, che può essere considerata come un secondo effetto associato alla mutazione nel gene Fratassina. Similmente a quanto osservato nel locus FMR1 (Gerhardt et al. 2014), in questo lavoro sono stati identificati eventi di arresto/pausa delle forche in corrispondenza della corta ripetizione GAA in una delle due linee di controllo analizzate, osservazione che suggerisce un possibile ruolo del tratto ripetuto non patologico sulla progressione delle forche. Recentemente è stato dimostrato che la sequenza GAA espansa è un sito di blocco delle forche replicative, ed è stato ipotizzato che gli eventi di arresto siano dovuti alla collisione tra i complessi proteici coinvolti nella replicazione e nella trascrizione del DNA (Gerhardt et al. 2016). Indagini future devono mirare a capire se il meccanismo di origin-switch osservato in presenza dell’espansione GAA sia la causa dell’espansione stessa o ne sia una conseguenza.
Un secondo aspetto che ho considerato riguarda la modulazione del programma replicativo in seguito a innalzamento e sbilanciamento dei pool dei nucleotidi. Sintesi, degradazione e consumo dei precursori del DNA devono essere accuratamente controllati per assicurare la replicazione completa del genoma e per evitare instabilità (Rampazzo et al. 2010; Chabes & Stillman 2007; Chabosseau et al. 2011; Bester et al. 2011). In presenza di quantità limitate di nucleotidi le forche replicative rallentano drasticamente e inducono l’attivazione della risposta al danno del DNA, sottoponendo le cellule a stress replicativo (Anglana et al. 2003; Courbet et al. 2008). Al contrario, le conseguenze di un elevato supporto di nucleotidi sulle dinamiche di replicazione sono state osservate solo in lievito, dove in seguito a sovraespressione dell’enzima ribonucleotide reduttasi è stato dimostrato un aumento della velocità di progressione delle forche (Poli et al. 2012). Gli effetti in cellule di mammifero sono invece ancora sconosciuti. Per questo motivo ho utilizzato come modelli sperimentali fibroblasti primari umani e monociti della linea THP1 con pool nucleotidici alti e sbilanciati a causa della mancanza della proteina SAMHD1 (Franzolin et al. 2013; Miazzi et al. 2014). Con la tecnica del molecular combing mi è stato possibile studiare i profili di replicazione a livello di intero genoma. Ho dimostrato che lo sbilanciamento dei pool dei nucleotidi non influisce sulle dinamiche di replicazione dei fibroblasti primari, né in condizioni fisiologiche né sotto stress replicativo. Al contrario, i monociti THP1 privi di SAMHD1 mostrano un inatteso rallentamento delle forche replicative con conseguente aumento delle origini attivate in ogni cluster. La diversa risposta cellulare osservata in seguito allo sbilanciamento dei pool può essere spiegata da un ruolo specifico di SAMHD1 in funzione del tipo cellulare. In alternativa, è possibile che i fibroblasti abbiano sviluppato un fenotipo adattativo per compensare la mancanza della proteina. Analisi future avranno come scopo quello di verificare la validità di queste due ipotesi e di valutare possibili effetti associati a blocco e ripartenza delle forche replicative.
Infine, ho valutato come cambiano i profili di replicazione durante il differenziamento. È noto che timing e dinamiche di replicazione sono specifici del tipo cellulare e sono regolati in base a cambiamenti dell’organizzazione cromatinica che avvengono durante lo sviluppo e il differenziamento (Palumbo et al. 2013; Hiratani et al. 2010; Hiratani et al. 2008). Quindi, ho valutato se la riattivazione forzata del ciclo cellulare in cellule terminalmente differenziate influenzi la replicazione del DNA. Come modello sperimentale ho usato miotubi di topo forzati a rientrare nel ciclo cellulare e li ho analizzati con molecular combing rispetto a mioblasti proliferanti. In seguito a riattivazione forzata, ho osservato una significativa riduzione della velocità delle forche replicative, similmente a quanto visto in condizioni di stress replicativo (Anglana et al. 2003; Palumbo et al. 2010). Questo risultato è in accordo con il fallimento del processo replicativo osservato nei miotubi riattivati e si pensa sia dovuto a un’incapacità di queste cellule di espandere in modo corretto i pool dei nucleotidi (Pajalunga et al. 2010; Pajalunga et al. 2017). In effetti, dopo l’aggiunta dei precursori del DNA nei miotubi riattivati si osserva un parziale miglioramento della velocità delle forche. Nonostante ciò però, il numero di origini attivate in ogni cluster è simile tra miotubi e mioblasti, perciò è ragionevole pensare che regioni del genoma restino non replicate. In conclusione, l’incapacità di completare la replicazione del DNA osservata nei miotubi dopo riattivazione forzata del ciclo cellulare non solo è dovuta alla limitata disponibilità di nucleotidi, ma anche a un difetto nel reclutare origini di replicazione aggiuntive per compensare la riduzione delle velocità. Un secondo aspetto interessante è l'aumentata proporzione di forche unidirezionali nei miotubi riattivati rispetto ai mioblasti, simile a quanto precedentemente osservato in fibroblasti primari umani (Palumbo et al. 2013). In questo caso, le forche unidirezionali visualizzate possono essere considerate come un residuo della modalità con cui alcuni domini replicano quando le cellule vanno verso il differenziamento terminale. Resta interessante capire se anche il timing della replicazione sia alterato dopo riattivazione forzata del ciclo cellulare.
La replicazione del DNA è un processo molto complesso caratterizzato da una grande plasticità, pertanto non è consigliato trarre conclusioni generali da studi basati su singoli tipi cellulari. I risultati ottenuti in questo lavoro contribuiscono a interpretare la grande complessità del processo replicativo, offrendo anche nuove prospettive per approfondimenti futuri.

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EPrint type:Ph.D. thesis
Tutor:Russo, Antonella
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:24 January 2017
Anno di Pubblicazione:24 January 2017
Key Words:replicazione del DNA; differenziamento; riattivazione ciclo cellulare; espansione di triplette ripetute; analisi di replicazione; DNA replication; replication timing; molecular combing; FXN; Friedreich's ataxia; SAMHD1; terminal differentiation; cell cycle reactivation; FACS sorting; SNS abundance assay; FISH; trinucleotide repeat expansion disease; TNR expansion; replication analysis.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9899
Depositato il:02 Nov 2017 15:35
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