Bibliografías temáticas / Replisome

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Literatura académica sobre el tema "Replisome"

Autor: Grafiati
Publicado: 4 de junio de 2021
Última modificación: 25 de mayo de 2024

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Artículos de revistas sobre el tema "Replisome"

1

Galarreta, Antonio, Pablo Valledor, Oscar Fernandez-Capetillo y Emilio Lecona. "Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1". International Journal of Molecular Sciences 22, n.º 16 (16 de agosto de 2021): 8796. http://dx.doi.org/10.3390/ijms22168796.

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Post-translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitin-mediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage.
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2

Priego Moreno, Sara, Rebecca M. Jones, Divyasree Poovathumkadavil, Shaun Scaramuzza y Agnieszka Gambus. "Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity". Life Science Alliance 2, n.º 2 (abril de 2019): e201900390. http://dx.doi.org/10.26508/lsa.201900390.

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We have shown previously that the process of replication machinery (replisome) disassembly at the termination of DNA replication forks in the S-phase is driven through polyubiquitylation of one of the replicative helicase subunits (Mcm7) by Cul2LRR1 ubiquitin ligase. Interestingly, upon inhibition of this pathway in Caenorhabditis elegans embryos, the replisomes retained on chromatin were unloaded in the subsequent mitosis. Here, we show that this mitotic replisome disassembly pathway exists in Xenopus laevis egg extract and we determine the first elements of its regulation. The mitotic disassembly pathway depends on the formation of K6- and K63-linked ubiquitin chains on Mcm7 by TRAIP ubiquitin ligase and the activity of p97/VCP protein segregase. Unlike in lower eukaryotes, however, it does not require SUMO modifications. Importantly, we also show that this process can remove all replisomes from mitotic chromatin, including stalled ones, which indicates a wide application for this pathway over being just a “backup” for terminated replisomes. Finally, we characterise the composition of the replisome retained on chromatin until mitosis.
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3

Li, Huilin, Nina Y. Yao y Michael E. O'Donnell. "Anatomy of a twin DNA replication factory". Biochemical Society Transactions 48, n.º 6 (10 de diciembre de 2020): 2769–78. http://dx.doi.org/10.1042/bst20200640.

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The replication of DNA in chromosomes is initiated at sequences called origins at which two replisome machines are assembled at replication forks that move in opposite directions. Interestingly, in vivo studies observe that the two replication forks remain fastened together, often referred to as a replication factory. Replication factories containing two replisomes are well documented in cellular studies of bacteria (Escherichia coli and Bacillus subtilis) and the eukaryote, Saccharomyces cerevisiae. This basic twin replisome factory architecture may also be preserved in higher eukaryotes. Despite many years of documenting the existence of replication factories, the molecular details of how the two replisome machines are tethered together has been completely unknown in any organism. Recent structural studies shed new light on the architecture of a eukaryote replisome factory, which brings with it a new twist on how a replication factory may function.
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4

Kapadia, Nitin y Rodrigo Reyes-Lamothe. "A quest for coordination among activities at the replisome". Biochemical Society Transactions 47, n.º 4 (8 de agosto de 2019): 1067–75. http://dx.doi.org/10.1042/bst20180402.

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Abstract Faithful DNA replication is required for transmission of the genetic material across generations. The basic mechanisms underlying this process are shared among all organisms: progressive unwinding of the long double-stranded DNA; synthesis of RNA primers; and synthesis of a new DNA chain. These activities are invariably performed by a multi-component machine called the replisome. A detailed description of this molecular machine has been achieved in prokaryotes and phages, with the replication processes in eukaryotes being comparatively less known. However, recent breakthroughs in the in vitro reconstitution of eukaryotic replisomes have resulted in valuable insight into their functions and mechanisms. In conjunction with the developments in eukaryotic replication, an emerging overall view of replisomes as dynamic protein ensembles is coming into fruition. The purpose of this review is to provide an overview of the recent insights into the dynamic nature of the bacterial replisome, revealed through single-molecule techniques, and to describe some aspects of the eukaryotic replisome under this framework. We primarily focus on Escherichia coli and Saccharomyces cerevisiae (budding yeast), since a significant amount of literature is available for these two model organisms. We end with a description of the methods of live-cell fluorescence microscopy for the characterization of replisome dynamics.
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5

Chang, Seungwoo, Karel Naiman, Elizabeth S. Thrall, James E. Kath, Slobodan Jergic, Nicholas E. Dixon, Robert P. Fuchs y Joseph J. Loparo. "A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes". Proceedings of the National Academy of Sciences 116, n.º 51 (3 de diciembre de 2019): 25591–601. http://dx.doi.org/10.1073/pnas.1914485116.

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DNA lesions stall the replisome and proper resolution of these obstructions is critical for genome stability. Replisomes can directly replicate past a lesion by error-prone translesion synthesis. Alternatively, replisomes can reprime DNA synthesis downstream of the lesion, creating a single-stranded DNA gap that is repaired primarily in an error-free, homology-directed manner. Here we demonstrate how structural changes within theEscherichia colireplisome determine the resolution pathway of lesion-stalled replisomes. This pathway selection is controlled by a dynamic interaction between the proofreading subunit of the replicative polymerase and the processivity clamp, which sets a kinetic barrier to restrict access of translesion synthesis (TLS) polymerases to the primer/template junction. Failure of TLS polymerases to overcome this barrier leads to repriming, which competes kinetically with TLS. Our results demonstrate that independent of its exonuclease activity, the proofreading subunit of the replisome acts as a gatekeeper and influences replication fidelity during the resolution of lesion-stalled replisomes.
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6

Jenkyn-Bedford, Michael, Morgan L. Jones, Yasemin Baris, Karim P. M. Labib, Giuseppe Cannone, Joseph T. P. Yeeles y Tom D. Deegan. "A conserved mechanism for regulating replisome disassembly in eukaryotes". Nature 600, n.º 7890 (26 de octubre de 2021): 743–47. http://dx.doi.org/10.1038/s41586-021-04145-3.

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AbstractReplisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45–MCM–GINS (CMG) replicative helicase1–3. Despite being driven by evolutionarily diverse E3 ubiquitin ligases in different eukaryotes (SCFDia2 in budding yeast1, CUL2LRR1 in metazoa4–7), replisome disassembly is governed by a common regulatory principle, in which ubiquitylation of CMG is suppressed before replication termination, to prevent replication fork collapse. Recent evidence suggests that this suppression is mediated by replication fork DNA8–10. However, it is unknown how SCFDia2 and CUL2LRR1 discriminate terminated from elongating replisomes, to selectively ubiquitylate CMG only after termination. Here we used cryo-electron microscopy to solve high-resolution structures of budding yeast and human replisome–E3 ligase assemblies. Our structures show that the leucine-rich repeat domains of Dia2 and LRR1 are structurally distinct, but bind to a common site on CMG, including the MCM3 and MCM5 zinc-finger domains. The LRR–MCM interaction is essential for replisome disassembly and, crucially, is occluded by the excluded DNA strand at replication forks, establishing the structural basis for the suppression of CMG ubiquitylation before termination. Our results elucidate a conserved mechanism for the regulation of replisome disassembly in eukaryotes, and reveal a previously unanticipated role for DNA in preserving replisome integrity.
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7

Lewis, Jacob S., Lisanne M. Spenkelink, Grant D. Schauer, Flynn R. Hill, Roxanna E. Georgescu, Michael E. O’Donnell y Antoine M. van Oijen. "Single-molecule visualization of Saccharomyces cerevisiae leading-strand synthesis reveals dynamic interaction between MTC and the replisome". Proceedings of the National Academy of Sciences 114, n.º 40 (18 de septiembre de 2017): 10630–35. http://dx.doi.org/10.1073/pnas.1711291114.

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The replisome, the multiprotein system responsible for genome duplication, is a highly dynamic complex displaying a large number of different enzyme activities. Recently, the Saccharomyces cerevisiae minimal replication reaction has been successfully reconstituted in vitro. This provided an opportunity to uncover the enzymatic activities of many of the components in a eukaryotic system. Their dynamic behavior and interactions in the context of the replisome, however, remain unclear. We use a tethered-bead assay to provide real-time visualization of leading-strand synthesis by the S. cerevisiae replisome at the single-molecule level. The minimal reconstituted leading-strand replisome requires 24 proteins, forming the CMG helicase, the Pol ε DNA polymerase, the RFC clamp loader, the PCNA sliding clamp, and the RPA single-stranded DNA binding protein. We observe rates and product lengths similar to those obtained from ensemble biochemical experiments. At the single-molecule level, we probe the behavior of two components of the replication progression complex and characterize their interaction with active leading-strand replisomes. The Minichromosome maintenance protein 10 (Mcm10), an important player in CMG activation, increases the number of productive replication events in our assay. Furthermore, we show that the fork protection complex Mrc1–Tof1–Csm3 (MTC) enhances the rate of the leading-strand replisome threefold. The introduction of periods of fast replication by MTC leads to an average rate enhancement of a factor of 2, similar to observations in cellular studies. We observe that the MTC complex acts in a dynamic fashion with the moving replisome, leading to alternating phases of slow and fast replication.
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8

Wang, Jue D., Megan E. Rokop, Melanie M. Barker, Nathaniel R. Hanson y Alan D. Grossman. "Multicopy Plasmids Affect Replisome Positioning in Bacillus subtilis". Journal of Bacteriology 186, n.º 21 (1 de noviembre de 2004): 7084–90. http://dx.doi.org/10.1128/jb.186.21.7084-7090.2004.

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ABSTRACT The DNA replication machinery, various regions of the chromosome, and some plasmids occupy characteristic subcellular positions in bacterial cells. We visualized the location of a multicopy plasmid, pHP13, in living cells of Bacillus subtilis using an array of lac operators and LacI-green fluorescent protein (GFP). In the majority of cells, plasmids appeared to be highly mobile and randomly distributed. In a small fraction of cells, there appeared to be clusters of plasmids located predominantly at or near a cell pole. We also monitored the effects of the presence of multicopy plasmids on the position of DNA polymerase using a fusion of a subunit of DNA polymerase to GFP. Many of the plasmid-containing cells had extra foci of the replisome, and these were often found at uncharacteristic locations in the cell. Some of the replisome foci were dynamic and highly mobile, similar to what was observed for the plasmid. In contrast, replisome foci in plasmid-free cells were relatively stationary. Our results indicate that in B. subtilis, plasmid-associated replisomes are recruited to the subcellular position of the plasmid. Extending this notion to the chromosome, we postulated that the subcellular position of the chromosomally associated replisome is established by the subcellular location of oriC at the time of initiation of replication.
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9

Nye, Dillon B. y Nathan A. Tanner. "Chimeric DNA byproducts in strand displacement amplification using the T7 replisome". PLOS ONE 17, n.º 9 (19 de septiembre de 2022): e0273979. http://dx.doi.org/10.1371/journal.pone.0273979.

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Recent advances in next generation sequencing technologies enable reading DNA molecules hundreds of kilobases in length and motivate development of DNA amplification methods capable of producing long amplicons. In vivo, DNA replication is performed not by a single polymerase enzyme, but multiprotein complexes called replisomes. Here, we investigate strand-displacement amplification reactions using the T7 replisome, a macromolecular complex of a helicase, a single-stranded DNA binding protein, and a DNA polymerase. The T7 replisome may initiate processive DNA synthesis from DNA nicks, and the reaction of a 48 kilobase linear double stranded DNA substrate with the T7 replisome and nicking endonucleases is shown to produce discrete DNA amplicons. To gain a mechanistic understanding of this reaction, we utilized Oxford Nanopore long-read sequencing technology. Sequence analysis of the amplicons revealed chimeric DNA reads and uncovered a connection between template switching and polymerase exonuclease activity. Nanopore sequencing provides insight to guide the further development of isothermal amplification methods for long DNA, and our results highlight the need for high-specificity, high-turnover nicking endonucleases to initiate DNA amplification without thermal denaturation.
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10

Attali, Ilan, Michael R. Botchan y James M. Berger. "Structural Mechanisms for Replicating DNA in Eukaryotes". Annual Review of Biochemistry 90, n.º 1 (20 de junio de 2021): 77–106. http://dx.doi.org/10.1146/annurev-biochem-090120-125407.

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The faithful and timely copying of DNA by molecular machines known as replisomes depends on a disparate suite of enzymes and scaffolding factors working together in a highly orchestrated manner. Large, dynamic protein–nucleic acid assemblies that selectively morph between distinct conformations and compositional states underpin this critical cellular process. In this article, we discuss recent progress outlining the physical basis of replisome construction and progression in eukaryotes.
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Tesis sobre el tema "Replisome"

1

Traylen, Christopher. "To elucidate the Epstein-Barr virus replisome". Thesis, University of Sussex, 2016. http://sro.sussex.ac.uk/id/eprint/59420/.

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Epstein-Barr virus (EBV) is a member of the γ-herpesvirus subfamily of Herpesviridae. EBV is a double stranded DNA virus infecting humans causing a variety of disease from asymptomatic infection to association with certain tumours including Burkitts lymphoma, Hodgkin's disease and nasopharyngeal carcinoma. EBV encodes an immediate-early protein called Zta (BZLF1, EB1, ZEBRA), which is an important transcription factor and replication factor direct in disrupting latency. EBV encodes viral proteins that assemble as a replisome at the viral lytic origin recognition site (Ori-Lyt). Zta binds Ori-Lyt and it is unclear how Zta interacts and recruits the complex to the site of DNA replication, while coordinating and recruiting host factors. After a mutation to three alanines (ZtaAAA) data implicates that the extreme C-terminus of Zta is essential for replication. The question posed is how does Zta assemble the replisome? Identification of the lytic changes that contribute to lytic replication, including cellular components that may contribute to EBV replication is attempted. Transfected control, Zta and ZtaAAA in HEK293-BZLF1-KO cells was compared. Size exclusion chromatography identified a higher molecular weight complex containing Zta during viral replication. SILAC (Stable isotope labelling by amino acids in cell culture) coupled to proteomics analysis identified the elution fraction composition. An interpretation of these cellular components in the context of lytic replication is explored. Identification of interactions of Zta with cellular proteins was attempted by SILAC histidine tagged Zta with pull down assay. Quantitative data was returned and a confirmation of interactions was attempted. A global proteomics approach was also performed. An enrichment method to isolate SILAC labeled Burkitts Lymphoma cells undergoing EBV lytic replication was coupled to mass spectrometry analysis to identify changes in host and viral proteins. Overall, cellular targets that may interact with Zta are to be confirmed. The global proteomics study recognized for the first time by proteomic analysis the identification of three EBV lytic replication cycle proteins.
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2

Reyes, Rodrigo. "Replisome Dynamics ans Chromosome Segregation in Escherichia Coli". Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490350.

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Replication of the chromosome of E. coli starts at a single point and proceeds bidirectionally until the replication forks meet at the opposite side of the DNA molecule. All this occurs on a compacted (around 1000-fold) chromosomal DNA, which is also organized in a manner that reflects the genetic position of the loci. Any roles that DNA replication plays in helping segregate the new DNA molecules, and how replication relates to nucleoid organization, remain to be understood.
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3

Morohashi, Hiroko. "SCF dia2 Associates with REplisome Progression Complexes During S Phase". Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492772.

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Emptage, Kieran. "Role of replisome proteins in recognition of deaminated bases in Archaea". Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493233.

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Family B DNA polymerases from archaea, such as Pyrococcus furiosus (Pfli-Pol), stall replication upon encountering template strand uracil and hypoxanthine (the deamination products of cytosine and adenine spectively) four base pairs ahead of the primer template junction. The deaminated bases bind to a specialized pocket within the amino terminal domain of the polymerase. This read-ahead mechanism could be a final attempt to detect deaminated bases and repair them by an as yet undetermined pathway, preventing 50% of the progeny inheriting a transition mutation.
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5

Hamilton, Nicklas Alexander. "Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes". PDXScholar, 2019. https://pdxscholar.library.pdx.edu/open_access_etds/5064.

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All living organisms need to accurately replicate their genome to survive. Genomic replication occurs in three phases; initiation, elongation, and completion. While initiation and elongation have been extensively characterized, less is known about how replication completes. In Escherichia coli completion occurs at sites where two replication forks converge and is proposed to involve the transiently bypass of the forks, before the overlapping sequences are resected and joined. The reaction requires RecBCD, and involves several other gene products including RecG, ExoI, and SbcDC but can occur independent of recombination or RecA. While several proteins are known to be involved, how they promote this reaction and the intermediates that arise remain uncharacterized. In the first part of this work, I describe the construction of plasmid "mini-chromosomes" containing a bidirectional origin of replication that can be used to examine the intermediates and factors required for the completion reaction. I verify that these substrates can be used to study the completion reaction by demonstrating that these plasmids require completion enzymes to propagate in cells. The completion enzymes are required for plasmids containing two-replisomes, but not one replisome, indicating that the substrate these enzymes act upon in vivo is specifically created when two replication forks converge. Completion events in E. coli are localized to one of the six termination (ter) sequences within the 400-kb terminus region due to the autoregulated action of Tus, which binds to ter and inhibits replication fork progression in an orientation-dependent manner. In the second part of this work, I examine how the presence of ter sequences affect completion on the 2-replisome plasmid. I show that addition of ter sequences modestly decreases the stability of the two-replisome plasmid and that this correlates with higher levels of abnormal, amplified molecules. The results support the idea that ter sites are not essential to completion of DNA replication; similar to what is seen on the chromosome. Rec-B-C-D forms a helicase-nuclease complex that, in addition to completion, is also required for double-strand break repair in E. coli. RecBCD activity is altered upon encountering specific DNA sequences, termed chi, in a manner that promotes crossovers during recombinational processes. In the third part of this work, I demonstrate that the presence of chi in a bidirectional plasmid model promotes the appearance of over-replicated linear molecules and that these products correlate with a reduced stability of the plasmid. The effect appears specific to plasmids containing two replisomes, as chi on the leading or lagging strand of plasmids containing one replisome had no-effect. The observation implies chi promotes a reaction that may encourage further synthesis during the completion reaction, and that at least on the mini-chromosomes substrates, this appears to be a destabilizing force.
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6

Heller, Ryan C. "Mechanisms of replisome assembly and stalled fork reactivation at DNA replication blocks /". Access full-text from WCMC:, 2006. http://proquest.umi.com/pqdweb?did=1296086331&sid=9&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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Mukherjee, Progya. "In vitro reconstitution of the ubiquitylation and disassembly of the eukaryotic replisome". Thesis, University of Dundee, 2018. https://discovery.dundee.ac.uk/en/studentTheses/1ad1c2bd-1d21-4f9e-bf76-eaad19fcf2d6.

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Maintenance of genomic integrity is dependent on the duplication of chromosomes, only once per cell cycle. Highly conserved mechanisms for the regulation of chromosome replication exists to ensure that the genome is copied only once. The Cdc45-MCM-GINS (CMG) DNA helicase which is the core of the eukaryotic replication complex, has been shown to be extensively regulated by post translational modifications, during its assembly. Therefore, it is not inconceivable that the process to unload the replication complex would also be a conserved and regulated process. In 2014, our lab discovered that the CMG complex undergoes post-translational modification in the form of ubiquitylation on one of the subunits of CMG, leading to its disassembly from the chromatin. Though the main players in the disassembly of CMG were known, viz the E3 ligase SCFDia2 and segregase Cdc48, very little was known about the mechanism of CMG disassembly. In the process of learning more about the disassembly of the replicative helicase from chromatin, I reconstituted the ubiquitylation of CMG and thereafter the disassembly of CMG helicase in vitro. My work resulting in the reconstitution of CMG disassembly in vitro is the first example of the disassembly of a multi-subunit physiological substrate of Cdc48. Though CMG is ubiquitylated in yeast extracts in vitro, it does not lead to its disassembly and therefore led me to find conditions necessary for the efficient ubiquitylation of CMG. I have further shown that purifying the E3 ligase associated CMG can be efficiently ubiquitylated in a semi-reconstituted system consisting of purified factors, necessary for the ubiquitylation of substrate. I investigated whether this efficiently ubiquitylated CMG can be disassembled by purified Cdc48 and associated co-factor Ufd1/Npl4 in vitro and found that disassembly is dependent on K48 linked poly-ubiquitylation of CMG. I have found that the reconstituted poly-ubiquitylation of CMG is restricted to the Mcm7 subunit of CMG, recapitulating the ubiquitylation of CMG in vivo, and my data points out that there are multiple sites of ubiquitylation on Mcm7. Through this work, I have also found that ubiquitylated Mcm7 no longer associates with the rest of the CMG components after disassembly of CMG. My assays and findings, open the door towards dissecting the molecular mechanism of the disassembly of CMG in greater detail.
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8

Grgurevic, Srdana. "Characterization of DNA replication control mechanisms involved in evolution and therapeutic resistance of chronic lymphocytic leukemia". Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30386.

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La leucémie lymphoïde chronique (LLC) est l'hémopathie maligne la plus commune chez les adultes dans les pays occidentaux. La LLC est caractérisée par une instabilité génomique qui se présente sous la forme de mutations somatiques récurrentes et d'anomalies chromosomiques. L'évolution clinique de la maladie, ainsi que la réponse au traitement basé sur la fludarabine, est très hétérogène. Bien que le traitement chimiothérapeutique de première ligne soit relativement efficace, la rechute est inévitable. Par conséquent, la LLC reste une maladie incurable. Les voies dites "3R", réplication, réparation et recombinaison de l'ADN, sont des processus essentiels pour maintenir l'intégrité du génome et prévenir l'apparition du cancer. A contrario, l'instabilité génétique peut entraîner la tumorigenèse et soutenir le développement de la chimiorésistance. Le but de mon projet de thèse a été d'étudier comment les 3R pouvaient contribuer à l'évolution de la LLC. L'analyse de l'expression génique à haut débit, a montré une signature 3R spécifique dans la LLC. De plus, en utilisant des données cliniques nous avons pu: 1. révéler l'anti-silencing function 1A histone chaperone (ASF1A) comme un marqueur pronostique pour le temps de début du premier traitement (time to first treatment (TTFT)) indépendamment des autres marqueurs cliniques connus, 2. montrer que le niveau d'expression de l'ADN polymérase nu (POLN) avant un traitement à base de fludarabine conditionne le temps sans progression (time to progression (TTP)) chez les patients après le traitement. Etant un analogue d'un nucléotide, la fludarabine agit, entre autres, comme un inhibiteur de la ribonucléotide réductase (RNR), une enzyme essentielle pour la régulation du pool cellulaire des désoxyribonucléotides triphosphates (dNTPs). Or, une modification du pool des dNTPs imposée par la fludarabine provoque un stress réplicatif en perturbant la synthèse d'ADN. Nos données suggèrent que Pol nu (Pol ?) peut diminuer ce stress réplicatif en activant de nouvelles origines de réplication. Dans ce contexte, nous démontrons, donc, le rôle de Pol ? dans la chimiorésistance à la fludarabine. En conclusion, notre étude a démontré l'implication des facteurs 3R dans l'évolution de la LLC précédent le traitement ainsi que leur rôle mécanistique dans la résistance à la chimiothérapie à base de fludarabine
Chronic lymphocytic leukemia (CLL), the most common type of adult leukemia in the Western world, is a hematological malignancy characterized by genomic instability present in form of common somatic mutations and chromosomal abnormalities. The disease has a heterogeneous clinical course and despite relatively efficacious first-line chemoimmunotherapeutic treatment based on fludarabine, majority of CLL patients still relapses. CLL, therefore, remains an incurable disease. DNA transactions, including replication, repair of damaged DNA and recombination (the so-called "3Rs") are crucial processes required for preserving genome integrity and limiting cancer risk. Genome instability, on the other hand, is known to drive tumorigenesis and contribute to development of chemoresistance. The aim of my thesis project was to explore whether and how 3R could contribute to the evolution of CLL. In our high-throughput gene expression analysis we defined a specific 3R CLL signature and revealed anti-silencing function 1A histone chaperon (ASF1A) as an independent prognostic marker of time to first treatment (TTFT). Moreover, clinical data analysis showed that DNA polymerase nu (POLN) gene expression level could determine time to progression (TTP) in patients treated with fludarabine based therapeutic regime. Fludarabine is a nucleotide analog that acts, among other, as an inhibitor of ribonucleotide reductase (RNR), an enzyme responsible for regulating the cellular deoxyribonucleotide triphosphate (dNTP) pool. Perturbation of the dNTP pool caused by treatment with fludarabine induces replication stress by arresting DNA synthesis processes. Our data suggest that Pol nu (Pol ?) can counteract this type of replication stress by supporting the activation of new replication origins and, thereby, drive fludarabine chemoresistance. In conclusion, our study, on one hand, demonstrated the implication of 3R factors in the clinical course of CLL before the chemoimmmunotherapy treatment and, on the other hand, revealed their mechanistic role in resistance to fludarabine based therapy
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9

Appanah, Rowin. "Replisome-mediated homeostasis of DNA/RNA hybrids in eukaryotic genomes is critical for cell fates and chromatin stability". Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/100501/.

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During DNA replication, forks often stall upon encountering obstacles blocking their progression. Cells will act to speedily remove or overcome such barriers, thus allowing complete synthesis of chromosomes. This is the case for R-loops, DNA/RNA hybrids that arise during transcription. One mechanism to remove such R-loops involve DNA/RNA helicases. Here, I have shown that one such helicase, Sen1, associates with replisome components during S phase in the model organism S. cerevisiae. I demonstrate that the N-terminal domain of Sen1 is both sufficient and necessary for the interaction of the protein with the replisome. I also identified Ctf4 as one of at least two replisome interactors of Sen1. By mutational analysis, a mutant of Sen1 (Sen1-3) that cannot interact with the replisome was created. This mutant is healthy on its own but is lethal in the absence of both RNase H1 and H2. Overexpression of the sen1-3 allele from the constitutive ACT1 promoter is able to suppress this synthetic lethality, suggesting that Sen1 travels with replisomes in order to be quickly recruited at sites of R-loops that impair fork progression so as to remove those R-loops. In some cases, cells exploit fork stalling for biologically important processes. This is the case in Sz. pombe, where an imprint prevents complete DNA replication, triggering cell-type switching. This imprint is dependent on Pol1, a component of the replisome. Importantly, a single imprinting-defective allele of pol1 has been identified to date. Using in vitro assays, I have shown that this Pol1 mutant has reduced affinity for its substrates and is a correspondingly poor polymerase. By generating novel alleles of pol1, I have also demonstrated that switching-deficiency correlates with the affinity of Pol1 for its substrates in vivo. Finally, two interactors of Pol1 (Mcl1Ctf4 and Spp1Pri1 ) have been shown to have switching defects. S. cerevisiae and Sz. pombe have similar yet distinct genetic nomenclature conventions. Given that both model organisms were used in this study, it is important to highlight the conventions for both organisms to prevent confusion. In S. cerevisiae, wildtype gene names are expressed as a three letter, uppercase and italic name followed by a number (e.g. SEN1). The three letter name often corresponds to the screen through which the gene in question was originally identified. Mutants are generally designated with the same three letter but in lower case (unless the mutant is dominant) and with an allele designation (e.g. sen1∆, sen1-1 and sen1-2). Because of historical context, the allele designations vary in format (e.g. leu2-3,112 is a mutant of LEU2). Protein names are given as a three letter name with the first letter in uppercase (e.g. Sen1). This is also true for mutant proteins, with the added allele designation (e.g Sen1-1 and Sen1-2). In this study, I have generated constructs of the SEN1 gene and these constructs are referred to as SEN1 (X-Y), where X and Y refer to the first and last residues being encoded for. The corresponding proteins are referred to as Sen1 (X-Y). Different promoters have been used and, where appropriate, the promoters are expressed similarly to their wildtype gene names (e.g. GAL1, SEN1 and ACT1). In Sz. pombe, wildtype gene names are expressed as a three letter, lowercase and italic name followed by a number (e.g. pol1). Mutants are generally designated in the same format but with an allele designation. Like in S. cerevisiae, the allele designation varies widely (e.g. pol1-1, pol1-H4 and pol1-ts13). Additionally, because of the historical context, some (but not all) alleles of pol1 are referred to as swi7 to reflect the fact that they are defective for cell-type switching. Similar to the situation in S. cerevisiae, proteins names are given as a three letter name with the first letter in uppercase for both wildtype and mutants (e.g. Pol1 and Swi7-1). Sometimes, for the sake of comparison, genes or proteins are referred to their S. cerevisiae orthologues (e.g. swi1TOF1 and Swi1Tof1 , respectively). Several protein tags have been used in this study. When written in gene form, they were written in capital letters and italicized, irrespective of the host (e.g. 5FLAG) and when in protein form, they were written in capital, irrespective of the host (e.g. 5FLAG).
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Jeiranian, Harout Arthur. "Use of Two-Dimensional Agarose-Gel Analysis to Characterize Processing of UV-Irradiated Plasmids and the Composition of the Replisome Following UV-induced Arrest". PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/921.

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In this thesis, I address two fundamental questions related to our understanding of how DNA damage is processed and repaired during replication. Using Two-dimensional (2-D) agarose gel analysis, I first examine whether DNA damage on plasmids introduced by transformation is processed in a manner similar to that observed on endogenously replicating plasmids and the chromosome. The original intent for using this approach was to develop a technique that could examine how different DNA adducts would be repaired in various sequence contexts. However, I found that distinct differences exist between the processing of DNA damage on transforming plasmids and the chromosome. The 2-D agarose gel analysis shows that RecA-mediated processing does not contribute to the survival of transforming plasmids and that this effect is likely due to inefficient replication of the plasmids after they are initially introduced into cells. These observations, while important, place limitations on the usefulness of transforming plasmids to characterize cellular repair processes. In a second question, I characterize the composition of the replisome following arrest by UV-induced DNA damage. Using 2-D agarose gel analysis the structural changes that occur in DNA during processing and repair have been well characterized, however, little is known about the fate of the replisome itself during these events. I used thermosensitive replication mutants to compare the DNA structural intermediates induced after disruption of specific components of the replisome to those observed after UV damage. The results show that dissociation of subunits required for polymerase stabilization are sufficient to induce the same processing events observed after UV damage. By contrast, disruption of the helicase-primase complex induces abnormal structures and a loss of replication integrity, suggesting that these components remain intact and bound to the template following replication arrest. I propose that polymerase dissociation provides a mechanism that allows repair proteins to gain access to the lesion while retention of the helicase serves to maintain the integrity and licensing of the fork so that replication can resume from the appropriate site once the lesion has been processed.
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Libros sobre el tema "Replisome"

1

MacNeill, Stuart, ed. The Eukaryotic Replisome: a Guide to Protein Structure and Function. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4572-8.

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Watching the Replisome: Single-molecule Studies of Eukaryotic DNA Replication. [New York, N.Y.?]: [publisher not identified], 2017.

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MacNeill, Stuart. Eukaryotic Replisome: A Guide to Protein Structure and Function. Springer Netherlands, 2014.

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MacNeill, Stuart. Eukaryotic Replisome: A Guide to Protein Structure and Function. Springer London, Limited, 2012.

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The Eukaryotic Replisome A Guide To Protein Structure And Function. Springer, 2012.

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Capítulos de libros sobre el tema "Replisome"

1

Lygerou, Zoi. "Replisome". En Encyclopedia of Systems Biology, 1847–48. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4419-9863-7_1441.

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Nelson, Scott W., Zhihao Zhuang, Michelle M. Spiering y Stephen J. Benkovic. "T4 Phage Replisome". En Viral Genome Replication, 337–64. Boston, MA: Springer US, 2009. http://dx.doi.org/10.1007/b135974_16.

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Bai, Lin, Zuanning Yuan, Jingchuan Sun, Roxana Georgescu, Michael E. O’Donnell y Huilin Li. "Architecture of the Saccharomyces cerevisiae Replisome". En Advances in Experimental Medicine and Biology, 207–28. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-6955-0_10.

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Zhang, Huidong. "Fate of DNA Replisome upon Encountering DNA Damage". En DNA Replication - Damage from Environmental Carcinogens, 15–19. Dordrecht: Springer Netherlands, 2015. http://dx.doi.org/10.1007/978-94-017-7212-9_3.

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Soultanas, Panos y Edward Bolt. "Helicase and Primase Interactions with Replisome Components and Accessory Factors". En Molecular Life Sciences, 1–7. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4614-6436-5_469-1.

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MacNeill, Stuart. "Composition and Dynamics of the Eukaryotic Replisome: A Brief Overview". En Subcellular Biochemistry, 1–17. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4572-8_1.

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Soultanas, Panos y Edward Bolt. "Helicase and Primase Interactions with Replisome Components and Accessory Factors". En Molecular Life Sciences, 510–15. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4614-1531-2_469.

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Gaimster, Hannah, Charles Winterhalter, Alan Koh y Heath Murray. "Visualizing the Replisome, Chromosome Breaks, and Replication Restart in Bacillus subtilis". En Methods in Molecular Biology, 263–76. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2221-6_18.

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Grabarczyk, Daniel B. "The Fork Protection Complex: A Regulatory Hub at the Head of the Replisome". En Subcellular Biochemistry, 83–107. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-00793-4_3.

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Ciesielski, Grzegorz L., Vesa P. Hytönen y Laurie S. Kaguni. "Biolayer Interferometry: A Novel Method to Elucidate Protein–Protein and Protein–DNA Interactions in the Mitochondrial DNA Replisome". En Methods in Molecular Biology, 223–31. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3040-1_17.

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Actas de conferencias sobre el tema "Replisome"

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Williams, Lance. "A Self-Replicating System of Ribosome and Replisome Factories". En Proceedings of the Artificial Life Conference 2016. Cambridge, MA: MIT Press, 2016. http://dx.doi.org/10.1162/978-0-262-33936-0-ch098.

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Williams, Lance. "A Self-Replicating System of Ribosome and Replisome Factories". En Proceedings of the Artificial Life Conference 2016. Cambridge, MA: MIT Press, 2016. http://dx.doi.org/10.7551/978-0-262-33936-0-ch098.

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Informes sobre el tema "Replisome"

1

Hamilton, Nicklas. Use of Two-replisome Plasmids to Characterize how Chromosome Replication Completes. Portland State University Library, enero de 2000. http://dx.doi.org/10.15760/etd.6940.

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Jeiranian, Harout. Use of Two-Dimensional Agarose-Gel Analysis to Characterize Processing of UV-Irradiated Plasmids and the Composition of the Replisome Following UV-induced Arrest. Portland State University Library, enero de 2000. http://dx.doi.org/10.15760/etd.921.

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