Academic literature on the topic 'Lagging-strand DNA synthesis'
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Journal articles on the topic "Lagging-strand DNA synthesis"
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Giannattasio, Michele, and Dana Branzei. "DNA Replication Through Strand Displacement During Lagging Strand DNA Synthesis in Saccharomyces cerevisiae." Genes 10, no. 2 (February 21, 2019): 167. http://dx.doi.org/10.3390/genes10020167.
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This review discusses a set of experimental results that support the existence of extended strand displacement events during budding yeast lagging strand DNA synthesis. Starting from introducing the mechanisms and factors involved in leading and lagging strand DNA synthesis and some aspects of the architecture of the eukaryotic replisome, we discuss studies on bacterial, bacteriophage and viral DNA polymerases with potent strand displacement activities. We describe proposed pathways of Okazaki fragment processing via short and long flaps, with a focus on experimental results obtained in Saccharomyces cerevisiae that suggest the existence of frequent and extended strand displacement events during eukaryotic lagging strand DNA synthesis, and comment on their implications for genome integrity.
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Hernandez, Alfredo J., Seung-Joo Lee, and Charles C. Richardson. "Primer release is the rate-limiting event in lagging-strand synthesis mediated by the T7 replisome." Proceedings of the National Academy of Sciences 113, no. 21 (May 9, 2016): 5916–21. http://dx.doi.org/10.1073/pnas.1604894113.
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DNA replication occurs semidiscontinuously due to the antiparallel DNA strands and polarity of enzymatic DNA synthesis. Although the leading strand is synthesized continuously, the lagging strand is synthesized in small segments designated Okazaki fragments. Lagging-strand synthesis is a complex event requiring repeated cycles of RNA primer synthesis, transfer to the lagging-strand polymerase, and extension effected by cooperation between DNA primase and the lagging-strand polymerase. We examined events controlling Okazaki fragment initiation using the bacteriophage T7 replication system. Primer utilization by T7 DNA polymerase is slower than primer formation. Slow primer release from DNA primase allows the polymerase to engage the complex and is followed by a slow primer handoff step. The T7 single-stranded DNA binding protein increases primer formation and extension efficiency but promotes limited rounds of primer extension. We present a model describing Okazaki fragment initiation, the regulation of fragment length, and their implications for coordinated leading- and lagging-strand DNA synthesis.
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Koussa, Natasha C., and Duncan J. Smith. "Limiting DNA polymerase delta alters replication dynamics and leads to a dependence on checkpoint activation and recombination-mediated DNA repair." PLOS Genetics 17, no. 1 (January 25, 2021): e1009322. http://dx.doi.org/10.1371/journal.pgen.1009322.
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DNA polymerase delta (Pol δ) plays several essential roles in eukaryotic DNA replication and repair. At the replication fork, Pol δ is responsible for the synthesis and processing of the lagging-strand. At replication origins, Pol δ has been proposed to initiate leading-strand synthesis by extending the first Okazaki fragment. Destabilizing mutations in human Pol δ subunits cause replication stress and syndromic immunodeficiency. Analogously, reduced levels of Pol δ in Saccharomyces cerevisiae lead to pervasive genome instability. Here, we analyze how the depletion of Pol δ impacts replication origin firing and lagging-strand synthesis during replication elongation in vivo in S. cerevisiae. By analyzing nascent lagging-strand products, we observe a genome-wide change in both the establishment and progression of replication. S-phase progression is slowed in Pol δ depletion, with both globally reduced origin firing and slower replication progression. We find that no polymerase other than Pol δ is capable of synthesizing a substantial amount of lagging-strand DNA, even when Pol δ is severely limiting. We also characterize the impact of impaired lagging-strand synthesis on genome integrity and find increased ssDNA and DNA damage when Pol δ is limiting; these defects lead to a strict dependence on checkpoint signaling and resection-mediated repair pathways for cellular viability.
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Lukac, David, Zuzana Machacova, and Pavel Moudry. "Emetine blocks DNA replication via proteosynthesis inhibition not by targeting Okazaki fragments." Life Science Alliance 5, no. 12 (September 9, 2022): e202201560. http://dx.doi.org/10.26508/lsa.202201560.
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DNA synthesis of the leading and lagging strands works independently and cells tolerate single-stranded DNA generated during strand uncoupling if it is protected by RPA molecules. Natural alkaloid emetine is used as a specific inhibitor of lagging strand synthesis, uncoupling leading and lagging strand replication. Here, by analysis of lagging strand synthesis inhibitors, we show that despite emetine completely inhibiting DNA replication: it does not induce the generation of single-stranded DNA and chromatin-bound RPA32 (CB-RPA32). In line with this, emetine does not activate the replication checkpoint nor DNA damage response. Emetine is also an inhibitor of proteosynthesis and ongoing proteosynthesis is essential for the accurate replication of DNA. Mechanistically, we demonstrate that the acute block of proteosynthesis by emetine temporally precedes its effects on DNA replication. Thus, our results are consistent with the hypothesis that emetine affects DNA replication by proteosynthesis inhibition. Emetine and mild POLA1 inhibition prevent S-phase poly(ADP-ribosyl)ation. Collectively, our study reveals that emetine is not a specific lagging strand synthesis inhibitor with implications for its use in molecular biology.
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Kramer, M. Gabriela, Saleem A. Khan, and Manuel Espinosa. "Lagging-Strand Replication from the ssoA Origin of Plasmid pMV158 in Streptococcus pneumoniae: In Vivo and In Vitro Influences of Mutations in Two ConservedssoA Regions." Journal of Bacteriology 180, no. 1 (January 1, 1998): 83–89. http://dx.doi.org/10.1128/jb.180.1.83-89.1998.
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ABSTRACT The streptococcal plasmid pMV158 replicates by the rolling-circle mechanism. One feature of this replication mechanism is the generation of single-stranded DNA intermediates which are converted to double-stranded molecules. Lagging-strand synthesis initiates from the plasmid single-stranded origin, sso. We have used the pMV158-derivative plasmid pLS1 (containing the ssoA type of lagging-strand origin) and a set of pLS1 derivatives with mutations in two conserved regions of the ssoA (the recombination site B [RSB] and a conserved 6-nucleotide sequence [CS-6]) to identify sequences important for plasmid lagging-strand replication inStreptococcus pneumoniae. Cells containing plasmids with mutations in the RSB accumulated 30-fold more single-stranded DNA than cells containing plasmids with mutations in the CS-6 sequence. Specificity of lagging-strand synthesis was tested by the development of a new in vitro replication system with pneumococcal cell extracts. Four major initiation sites of lagging-strand DNA synthesis were observed. The specificity of initiation was maintained in plasmids with mutations in the CS-6 region. Mutations in the RSB region, on the other hand, resulted in the loss of specific initiation of lagging-strand synthesis and also severely reduced the efficiency of replication.
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Spiering, Michelle M., Philip Hanoian, Swathi Gannavaram, and Stephen J. Benkovic. "RNA primer–primase complexes serve as the signal for polymerase recycling and Okazaki fragment initiation in T4 phage DNA replication." Proceedings of the National Academy of Sciences 114, no. 22 (May 15, 2017): 5635–40. http://dx.doi.org/10.1073/pnas.1620459114.
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The opposite strand polarity of duplex DNA necessitates that the leading strand is replicated continuously whereas the lagging strand is replicated in discrete segments known as Okazaki fragments. The lagging-strand polymerase sometimes recycles to begin the synthesis of a new Okazaki fragment before finishing the previous fragment, creating a gap between the Okazaki fragments. The mechanism and signal that initiate this behavior—that is, the signaling mechanism—have not been definitively identified. We examined the role of RNA primer–primase complexes left on the lagging ssDNA from primer synthesis in initiating early lagging-strand polymerase recycling. We show for the T4 bacteriophage DNA replication system that primer–primase complexes have a residence time similar to the timescale of Okazaki fragment synthesis and the ability to block a holoenzyme synthesizing DNA and stimulate the dissociation of the holoenzyme to trigger polymerase recycling. The collision with primer–primase complexes triggering the early termination of Okazaki fragment synthesis has distinct advantages over those previously proposed because this signal requires no transmission to the lagging-strand polymerase through protein or DNA interactions, the mechanism for rapid dissociation of the holoenzyme is always collision, and no unique characteristics need to be assigned to either identical polymerase in the replisome. We have modeled repeated cycles of Okazaki fragment initiation using a collision with a completed Okazaki fragment or primer–primase complexes as the recycling mechanism. The results reproduce experimental data, providing insights into events related to Okazaki fragment initiation and the overall functioning of DNA replisomes.
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Parenteau, Julie, and Raymund J. Wellinger. "Accumulation of Single-Stranded DNA and Destabilization of Telomeric Repeats in Yeast Mutant Strains Carrying a Deletion of RAD27." Molecular and Cellular Biology 19, no. 6 (June 1, 1999): 4143–52. http://dx.doi.org/10.1128/mcb.19.6.4143.
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ABSTRACT The Saccharomyces cerevisiae RAD27 gene encodes the yeast homologue of the mammalian FEN-1 nuclease, a protein that is thought to be involved in the processing of Okazaki fragments during DNA lagging-strand synthesis. One of the predicted DNA lesions occurring in rad27 strains is the presence of single-stranded DNA of the template strand for lagging-strand synthesis. We examined this prediction by analyzing the terminal DNA structures generated during telomere replication in rad27strains. The lengths of the telomeric repeat tracts were found to be destabilized in rad27 strains, indicating that naturally occurring direct repeats are subject to tract expansions and contractions in such strains. Furthermore, abnormally high levels of single-stranded DNA of the templating strand for lagging-strand synthesis were observed in rad27 cells. Overexpression of Dna2p in wild-type cells also yielded single-stranded DNA regions on telomeric DNA and caused a cell growth arrest phenotype virtually identical to that seen for rad27 cells grown at the restrictive temperature. Furthermore, overexpression of the yeast exonuclease Exo1p alleviated the growth arrest induced by both conditions, overexpression of Dna2p and incubation of rad27cells at 37°C. However, the telomere heterogeneity and the appearance of single-stranded DNA are not prevented by the overexpression of Exo1p in these strains, suggesting that this nuclease is not simply redundant with Rad27p. Our data thus provide in vivo evidence for the types of DNA lesions predicted to occur when lagging-strand synthesis is deficient and suggest that Dna2p and Rad27p collaborate in the processing of Okazaki fragments.
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Serra-Cardona, Albert, Chuanhe Yu, Xinmin Zhang, Xu Hua, Yuan Yao, Jiaqi Zhou, Haiyun Gan, and Zhiguo Zhang. "A mechanism for Rad53 to couple leading- and lagging-strand DNA synthesis under replication stress in budding yeast." Proceedings of the National Academy of Sciences 118, no. 38 (September 16, 2021): e2109334118. http://dx.doi.org/10.1073/pnas.2109334118.
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In response to DNA replication stress, DNA replication checkpoint kinase Mec1 phosphorylates Mrc1, which in turn activates Rad53 to prevent the generation of deleterious single-stranded DNA, a process that remains poorly understood. We previously reported that lagging-strand DNA synthesis proceeds farther than leading strand in rad53-1 mutant cells defective in replication checkpoint under replication stress, resulting in the exposure of long stretches of the leading-strand templates. Here, we show that asymmetric DNA synthesis is also observed in mec1-100 and mrc1-AQ cells defective in replication checkpoint but, surprisingly, not in mrc1∆ cells in which both DNA replication and checkpoint functions of Mrc1 are missing. Furthermore, depletion of either Mrc1 or its partner, Tof1, suppresses the asymmetric DNA synthesis in rad53-1 mutant cells. Thus, the DNA replication checkpoint pathway couples leading- and lagging-strand DNA synthesis by attenuating the replication function of Mrc1-Tof1 under replication stress.
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Sparks, Melanie A., Peter M. Burgers, and Roberto Galletto. "Pif1, RPA, and FEN1 modulate the ability of DNA polymerase δ to overcome protein barriers during DNA synthesis." Journal of Biological Chemistry 295, no. 47 (September 10, 2020): 15883–91. http://dx.doi.org/10.1074/jbc.ra120.015699.
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Successful DNA replication requires carefully regulated mechanisms to overcome numerous obstacles that naturally occur throughout chromosomal DNA. Scattered across the genome are tightly bound proteins, such as transcription factors and nucleosomes, that are necessary for cell function, but that also have the potential to impede timely DNA replication. Using biochemically reconstituted systems, we show that two transcription factors, yeast Reb1 and Tbf1, and a tightly positioned nucleosome, are strong blocks to the strand displacement DNA synthesis activity of DNA polymerase δ. Although the block imparted by Tbf1 can be overcome by the DNA-binding activity of the single-stranded DNA-binding protein RPA, efficient DNA replication through either a Reb1 or a nucleosome block occurs only in the presence of the 5'-3' DNA helicase Pif1. The Pif1-dependent stimulation of DNA synthesis across strong protein barriers may be beneficial during break-induced replication where barriers are expected to pose a problem to efficient DNA bubble migration. However, in the context of lagging strand DNA synthesis, the efficient disruption of a nucleosome barrier by Pif1 could lead to the futile re-replication of newly synthetized DNA. In the presence of FEN1 endonuclease, the major driver of nick translation during lagging strand replication, Pif1-dependent stimulation of DNA synthesis through a nucleosome or Reb1 barrier is prevented. By cleaving the short 5' tails generated during strand displacement, FEN1 eliminates the entry point for Pif1. We propose that this activity would protect the cell from potential DNA re-replication caused by unwarranted Pif1 interference during lagging strand replication.
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Nasheuer, Heinz Peter, and Nichodemus O. Onwubiko. "Lagging Strand Initiation Processes in DNA Replication of Eukaryotes—Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes." Genes 14, no. 5 (April 29, 2023): 1012. http://dx.doi.org/10.3390/genes14051012.
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In their influential reviews, Hanahan and Weinberg coined the term ‘Hallmarks of Cancer’ and described genome instability as a property of cells enabling cancer development. Accurate DNA replication of genomes is central to diminishing genome instability. Here, the understanding of the initiation of DNA synthesis in origins of DNA replication to start leading strand synthesis and the initiation of Okazaki fragment on the lagging strand are crucial to control genome instability. Recent findings have provided new insights into the mechanism of the remodelling of the prime initiation enzyme, DNA polymerase α-primase (Pol-prim), during primer synthesis, how the enzyme complex achieves lagging strand synthesis, and how it is linked to replication forks to achieve optimal initiation of Okazaki fragments. Moreover, the central roles of RNA primer synthesis by Pol-prim in multiple genome stability pathways such as replication fork restart and protection of DNA against degradation by exonucleases during double-strand break repair are discussed.
Dissertations / Theses on the topic "Lagging-strand DNA synthesis"
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Ononye, Onyekachi Ebelechukwu. "Defining the Role of Lysine Acetylation in Regulating the Fidelity of DNA Synthesis." Thesis, 2020. http://hdl.handle.net/1805/24762.
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Indiana University-Purdue University Indianapolis (IUPUI)Accurate DNA replication is vital for maintaining genomic stability. Consequently, the machinery required to drive this process is designed to ensure the meticulous maintenance of information. However, random misincorporation of errors reduce the fidelity of the DNA and lead to pre-mature aging and age-related disorders such as cancer and neurodegenerative diseases. Some of the incorporated errors are the result of the error prone DNA polymerase alpha (Pol α), which initiates synthesis on both the leading and lagging strand. Lagging strand synthesis acquires an increased number of polymerase α tracks because of the number of Okazaki fragments synthesized per round of the cell cycle (~50 million in mammalian cells). The accumulation of these errors invariably reduces the fidelity of the genome. Previous work has shown that these pol α tracks can be removed by two redundant pathways referred to as the short and long flap pathway. The long flap pathway utilizes a complex network of proteins to remove more of the misincorporated nucleotides than the short flap pathway which mediates the removal of shorter flaps. Lysine acetylation has been reported to modulate the function of the nucleases implicated in flap processing. The cleavage activity of the long flap pathway nuclease, Dna2, is stimulated by lysine acetylation while conversely lysine acetylation of the short flap pathway nuclease, FEN1, inhibits its activity. The major protein players implicated during Okazaki fragment processing (OFP) are known, however, the choice of the processing pathway and its regulation by lysine acetylation of its main players is yet unknown. This dissertation identifies three main findings: 1) Saccharomyces cerevisiae helicase, petite integration frequency (Pif1) is lysine acetylated by Esa1 and deacetylated by Rpd3 regulating its viability and biochemical properties including helicase, binding and ATPase activity ii) the single stranded DNA binding protein, human replication protein A (RPA) is modified by p300 and this modification stimulates its primary binding function and iii) lysine acetylated human RPA directs OFP towards the long flap pathway even for a subset of short flaps.
Book chapters on the topic "Lagging-strand DNA synthesis"
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Bauer, Glenn A., and Thomas Melendy. "Isolation and characterization of lagging strand processing activities." In Eukaryotic DNA Replication, 139–60. Oxford University PressOxford, 1999. http://dx.doi.org/10.1093/oso/9780199636815.003.0006.
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Abstract As a result of the bidirectional DNA replication process, lagging strand synthesis results in the formation of Okazaki fragments, hybrid polynucleotide molecules consisting of a short 5’ RNA primer and a long DNA extension. Lagging strand processing involves the removal of the RNA moiety from these fragments and the completion of DNA replication to synthesize a continuous DNA daughter molecule on the lagging strand at the replication fork.
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Anh, Tuan, Chul-Hwan Lee, and Yeon-Soo Seo. "Lagging Strand Synthesis and Genomic Stability." In DNA Repair - On the Pathways to Fixing DNA Damage and Errors. InTech, 2011. http://dx.doi.org/10.5772/22007.
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Papachristodoulou, Despo, Alison Snape, William H. Elliott, and Daphne C. Elliott. "DNA synthesis, repair, and recombination." In Biochemistry and Molecular Biology. Oxford University Press, 2018. http://dx.doi.org/10.1093/hesc/9780198768111.003.0027.
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This chapter considers DNA synthesis as semiconservative as it is catalysed by DNA polymerases, which require the four deoxyribonucleoside triphosphates, a template or parental strand to copy, and a primer. The chapter refers to the primer of prokaryotes which is synthesized by the primase enzyme and is a short RNA copy of part of the parental strand. Synthesis starts at a site of origin on the chromosome where strand separation occurs. The chapter notes that E. coli has a single site of origin while eukaryotic chromosomes have hundreds. The chapter clarifies how a helicase separates parental strands that produces supercoiling ahead of it, noting that supercoils are removed by topoisomerases. The problem of maintaining the 5′→3′ direction of synthesis of both strands is solved by continuous synthesis of the leading strand and discontinuous synthesis of the lagging strand.
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Lucchesi, John C. "Chromatin replication." In Epigenetics, Nuclear Organization & Gene Function, 165–72. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198831204.003.0014.
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During chromosome replication, each strand of the DNA serves as a template for the synthesis of a new strand (semiconservative replication). Replication originates with the binding of pre-replication complexes (MCM2–7) at multiple sites, termed origins of replication (ORIs). One strand of the parent DNA molecule (the leading strand) is replicated continuously in the 5´ to 3´ direction; the other, or lagging strand, is replicated one short segment at a time. These segments are referred to as Okazaki fragments, and their generation requires the synthesis of short complementary RNA primers. For replication to proceed, DNA must be unwound and freed from nucleosomes. After replication, the nucleosomal structure is re-established using a mixture of old and newly synthesized histones. DNA replication can encounter problems such as nucleotide depletion, DNA damage or topologically unfavorable structures that generate replication stress and replication fork stalling. The DNA replication process itself can also be subjected to errors. Cells have evolved a battery of mechanisms designed to bypass or repair damaged DNA strands.