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Genes & Genetic Systems 2016Camptothecin (CPT) inhibits DNA topoisomerase I (Top1) through a non-catalytic mechanism that stabilizes the Top1-DNA cleavage complex (Top1cc) and blocks the DNA... (Review)
Review
Camptothecin (CPT) inhibits DNA topoisomerase I (Top1) through a non-catalytic mechanism that stabilizes the Top1-DNA cleavage complex (Top1cc) and blocks the DNA re-ligation step, resulting in the accumulation in the genome of DNA single-strand breaks (SSBs), which are converted to secondary strand breaks when they collide with the DNA replication and RNA transcription machinery. DNA strand breaks mediated by replication, which have one DNA end, are distinct in repair from the DNA double-strand breaks (DSBs) that have two ends and are caused by ionizing radiation and other agents. In contrast to two-ended DSBs, such one-ended DSBs are preferentially repaired through the homologous recombination pathway. Conversely, the repair of one-ended DSBs by the non-homologous end-joining pathway is harmful for cells and leads to cell death. The choice of repair pathway has a crucial impact on cell fate and influences the efficacy of anticancer drugs such as CPT derivatives. In addition to replication-mediated one-ended DSBs, transcription also generates DNA strand breaks upon collision with the Top1cc. Some reports suggest that transcription-mediated DNA strand breaks correlate with neurodegenerative diseases. However, the details of the repair mechanisms of, and cellular responses to, transcription-mediated DNA strand breaks still remain unclear. In this review, combining our recent results and those of previous reports, we introduce and discuss the responses to CPT-induced DNA damage mediated by DNA replication and RNA transcription.
Topics: Camptothecin; DNA Breaks, Single-Stranded; DNA Repair; DNA Replication; DNA Topoisomerases, Type I; Humans; Transcription, Genetic
PubMed: 26616758
DOI: 10.1266/ggs.15-00023 -
International Journal of Molecular... Jun 2018Type IIA topoisomerases allow DNA double helical strands to pass through each other by generating transient DNA double strand breaks βDSBs), and in so doing, resolve... (Review)
Review
Type IIA topoisomerases allow DNA double helical strands to pass through each other by generating transient DNA double strand breaks βDSBs), and in so doing, resolve torsional strain that accumulates during transcription, DNA replication, chromosome condensation, chromosome segregation and recombination. Whereas most eukaryotes possess a single type IIA enzyme, vertebrates possess two distinct type IIA topoisomerases, Topo IIα and Topo IIβ. Although the roles of Topo IIα, especially in the context of chromosome condensation and segregation, have been well-studied, the roles of Topo IIβ are only beginning to be illuminated. This review begins with a summary of the initial studies surrounding the discovery and characterization of Topo IIβ and then focuses on the insights gained from more recent studies that have elaborated important functions for Topo IIβ in transcriptional regulation.
Topics: Animals; Chromosome Segregation; DNA Breaks, Double-Stranded; DNA Replication; DNA Topoisomerases, Type II; Humans; Transcription, Genetic
PubMed: 29966298
DOI: 10.3390/ijms19071917 -
Nucleic Acids Research May 2021Silver nanoclusters (AgNCs) have outstanding physicochemical characteristics, including the ability to interact with proteins and DNA. Given the growing number of...
Silver nanoclusters (AgNCs) have outstanding physicochemical characteristics, including the ability to interact with proteins and DNA. Given the growing number of diagnostic and therapeutic applications of AgNCs, we evaluated the impact of AgNCs on DNA replication and DNA damage response in cell-free extracts prepared from unfertilized Xenopus laevis eggs. We find that, among a number of silver nanomaterials, AgNCs uniquely inhibited genomic DNA replication and abrogated the DNA replication checkpoint in cell-free extracts. AgNCs did not affect nuclear membrane or nucleosome assembly. AgNCs-supplemented extracts showed a strong defect in the loading of the mini chromosome maintenance (MCM) protein complex, the helicase that unwinds DNA ahead of replication forks. FLAG-AgNCs immunoprecipitation and mass spectrometry analysis of AgNCs associated proteins demonstrated direct interaction between MCM and AgNCs. Our studies indicate that AgNCs directly prevent the loading of MCM, blocking pre-replication complex (pre-RC) assembly and subsequent DNA replication initiation. Collectively, our findings broaden the scope of silver nanomaterials experimental applications, establishing AgNCs as a novel tool to study chromosomal DNA replication.
Topics: Animals; DNA Replication; Minichromosome Maintenance Proteins; Nanostructures; Silver; Xenopus laevis
PubMed: 33905520
DOI: 10.1093/nar/gkab271 -
Trends in Parasitology Nov 2017In trypanosomatids, etiological agents of devastating diseases, replication is robust and finely controlled to maintain genome stability and function in stressful... (Review)
Review
In trypanosomatids, etiological agents of devastating diseases, replication is robust and finely controlled to maintain genome stability and function in stressful environments. However, these parasites encode several replication protein components and complexes that show potentially variant composition compared with model eukaryotes. This review focuses on the advances made in recent years regarding the differences and peculiarities of the replication machinery in trypanosomatids, including how such divergence might affect DNA replication dynamics and the replication stress response. Comparing the DNA replication machinery and processes of parasites and their hosts may provide a foundation for the identification of targets that can be used in the development of chemotherapies to assist in the eradication of diseases caused by these pathogens.
Topics: Animals; DNA Replication; Drug Delivery Systems; Host-Parasite Interactions; Humans; Protozoan Proteins; Research; Trypanosoma
PubMed: 28844718
DOI: 10.1016/j.pt.2017.08.002 -
EMBO Reports Apr 2010Although the basic mechanisms of DNA synthesis are conserved across species, there are differences between simple and complex organisms. In contrast to lower eukaryotes,... (Review)
Review
Although the basic mechanisms of DNA synthesis are conserved across species, there are differences between simple and complex organisms. In contrast to lower eukaryotes, replication origins in complex eukaryotes lack DNA sequence specificity, can be activated in response to stressful conditions and require poorly conserved factors for replication firing. The response to replication fork damage is monitored by conserved proteins, such as the TIPIN-TIM-CLASPIN complex. The absence of this complex induces severe effects on yeast replication, whereas in higher eukaryotes it is only crucial when the availability of replication origins is limiting. Finally, the dependence of DNA replication on homologous recombination proteins such as RAD51 and the MRE11-RAD50-NBS1 complex is also different; they are dispensable for yeast S-phase but essential for accurate DNA replication in metazoans under unchallenged conditions. The reasons for these differences are not yet understood. Here, we focus on some of these known unknowns of DNA replication.
Topics: Animals; DNA Replication; Eukaryota; Models, Biological; Yeasts
PubMed: 20203697
DOI: 10.1038/embor.2010.27 -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Animals; Cell Cycle Proteins; DNA Helicases; DNA Replication; Humans; Protein Serine-Threonine Kinases
PubMed: 24553113
DOI: 10.4161/cc.28212 -
BioEssays : News and Reviews in... Aug 2017Biochemical and cryo-electron microscopy studies have just been published revealing interactions among proteins of the yeast replisome that are important for highly... (Review)
Review
Arranging eukaryotic nuclear DNA polymerases for replication: Specific interactions with accessory proteins arrange Pols α, δ, and ϵ in the replisome for leading-strand and lagging-strand DNA replication.
Biochemical and cryo-electron microscopy studies have just been published revealing interactions among proteins of the yeast replisome that are important for highly coordinated synthesis of the two DNA strands of the nuclear genome. These studies reveal key interactions important for arranging DNA polymerases α, δ, and ϵ for leading and lagging strand replication. The CMG (Mcm2-7, Cdc45, GINS) helicase is central to this interaction network. These are but the latest examples of elegant studies performed in the recent past that lead to a much better understanding of how the eukaryotic replication fork achieves efficient DNA replication that is accurate enough to prevent diseases yet allows evolution.
Topics: Cryoelectron Microscopy; DNA Helicases; DNA Replication; DNA-Directed DNA Polymerase; Saccharomyces cerevisiae Proteins
PubMed: 28749073
DOI: 10.1002/bies.201700070 -
Genes & Genetic Systems Jan 2018Recent studies have indicated new roles for telomere-binding factors in the regulation of DNA replication, not only at the telomeres but also at the arm regions of the... (Review)
Review
Recent studies have indicated new roles for telomere-binding factors in the regulation of DNA replication, not only at the telomeres but also at the arm regions of the chromosome. Among these factors, Rif1, a conserved protein originally identified in yeasts as a telomere regulator, plays a major role in the spatiotemporal regulation of DNA replication during S phase. Its ability to interact with phosphatases and to create specific higher-order chromatin structures is central to the mechanism by which Rif1 exerts this function. In this review, we discuss recent progress in elucidating the roles of Rif1 and other telomere-binding factors in the regulation of chromosome events occurring at locations other than telomeres.
Topics: Animals; DNA Replication; Humans; S Phase; Telomere; Telomere-Binding Proteins
PubMed: 28674277
DOI: 10.1266/ggs.17-00008 -
Molecular Microbiology Dec 2008Bacteria that have a circular chromosome with a bidirectional DNA replication origin are thought to utilize a 'replication fork trap' to control termination of... (Review)
Review
Bacteria that have a circular chromosome with a bidirectional DNA replication origin are thought to utilize a 'replication fork trap' to control termination of replication. The fork trap is an arrangement of replication pause sites that ensures that the two replication forks fuse within the terminus region of the chromosome, approximately opposite the origin on the circular map. However, the biological significance of the replication fork trap has been mysterious, as its inactivation has no obvious consequence. Here we review the research that led to the replication fork trap theory, and we aim to integrate several recent findings that contribute towards an understanding of the physiological roles of the replication fork trap. Likely roles include the prevention of over-replication, and the optimization of post-replicative mechanisms of chromosome segregation, such as that involving FtsK in Escherichia coli.
Topics: Chromosome Segregation; Chromosomes, Bacterial; DNA Replication; Escherichia coli; Escherichia coli Proteins; Membrane Proteins; Models, Genetic
PubMed: 19019156
DOI: 10.1111/j.1365-2958.2008.06500.x -
Current Opinion in Genetics &... Apr 2009Replication timing is frequently discussed superficially in terms of its relationship to transcriptional activity via chromatin structure. However, so little is known... (Review)
Review
Replication timing is frequently discussed superficially in terms of its relationship to transcriptional activity via chromatin structure. However, so little is known about what regulates where and when replication initiates that it has been impossible to identify mechanistic and causal relationships. Moreover, much of our knowledge base has been anecdotal, derived from analyses of a few genes in unrelated cell lines. Recent studies have revisited long-standing hypotheses using genome-wide approaches. In particular, the foundation of this field was recently shored up with incontrovertible evidence that cellular differentiation is accompanied by coordinated changes in replication timing and transcription. These changes accompany subnuclear repositioning, and take place at the level of megabase-sized domains that transcend localized changes in chromatin structure or transcription. Inferring from these results, we propose that there exists a key transition during the middle of S-phase and that changes in replication timing traversing this period are associated with subnuclear repositioning and changes in the activity of certain classes of promoters.
Topics: Animals; Cell Differentiation; DNA Replication; DNA Replication Timing; Gene Expression Regulation; Humans; Isochores; S Phase; Transcription, Genetic
PubMed: 19345088
DOI: 10.1016/j.gde.2009.02.002