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  • 1
    Language: English
    In: Nature reviews. Cancer, 2016-01, Vol.16 (1), p.35-42
    Description: The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy.
    Subject(s): Animals ; Cancer ; Care and treatment ; DNA damage ; DNA Repair - physiology ; Gene mutations ; Genetic Research - history ; Genomic Instability - physiology ; Health aspects ; History, 20th Century ; Humans ; Methods ; Neoplasms - genetics ; Neoplasms - history ; Neoplasms - pathology
    ISSN: 1474-175X
    E-ISSN: 1474-1768
    Source: Nature Reviews
    Source: Get It Now
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  • 2
    Language: English
    In: Nature structural & molecular biology, 2015-03, Vol.22 (3), p.192-198
    Description: Three eukaryotic DNA polymerases are essential for genome replication. Polymerase (Pol) α-primase initiates each synthesis event and is rapidly replaced by processive DNA polymerases: Polɛ replicates the leading strand, whereas Polδ performs lagging-strand synthesis. However, it is not known whether this division of labor is maintained across the whole genome or how uniform it is within single replicons. Using Schizosaccharomyces pombe, we have developed a polymerase usage sequencing (Pu-seq) strategy to map polymerase usage genome wide. Pu-seq provides direct replication-origin location and efficiency data and indirect estimates of replication timing. We confirm that the division of labor is broadly maintained across an entire genome. However, our data suggest a subtle variability in the usage of the two polymerases within individual replicons. We propose that this results from occasional leading-strand initiation by Polδ followed by exchange for Polɛ.
    Subject(s): Analysis ; Deoxyribonucleic acid ; Division of labor ; DNA ; DNA - chemistry ; DNA biosynthesis ; DNA polymerase ; DNA Polymerase I - physiology ; DNA Polymerase II - physiology ; DNA Polymerase III - physiology ; DNA polymerases ; DNA replication ; DNA Replication - physiology ; DNA sequencing ; DNA-directed DNA polymerase ; Gene mapping ; Genetic aspects ; Genetic research ; Genomes ; Identification and classification ; Labor ; Maps ; Methods ; Models, Genetic ; Molecular biology ; Mutation ; Nucleotide sequencing ; Physiological aspects ; Primase ; Replication ; Replication Origin ; Replication origins ; Schizosaccharomyces - genetics ; Structure ; Yeast fungi ; Yeasts
    ISSN: 1545-9993
    E-ISSN: 1545-9985
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 3
    Language: English
    In: Nature communications, 2021-02-10, Vol.12 (1), p.923-923
    Description: Replication forks restarted by homologous recombination are error prone and replicate both strands semi-conservatively using Pol δ. Here, we use polymerase usage sequencing to visualize in vivo replication dynamics of HR-restarted forks at an S. pombe replication barrier, RTS1, and model replication by Monte Carlo simulation. We show that HR-restarted forks synthesise both strands with Pol δ for up to 30 kb without maturing to a δ/ε configuration and that Pol α is not used significantly on either strand, suggesting the lagging strand template remains as a gap that is filled in by Pol δ later. We further demonstrate that HR-restarted forks progress uninterrupted through a fork barrier that arrests canonical forks. Finally, by manipulating lagging strand resection during HR-restart by deleting pku70, we show that the leading strand initiates replication at the same position, signifying the stability of the 3' single strand in the context of increased resection.
    Subject(s): Communication and replication ; Deoxyribonucleic acid ; DNA ; DNA Replication ; DNA-Directed DNA Polymerase - genetics ; DNA-Directed DNA Polymerase - metabolism ; Homologous Recombination ; Homology ; Mathematical models ; Monte Carlo simulation ; Replication ; Replication forks ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Sequences ; Strands
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: PloS one, 2014, Vol.9 (12), p.e114749-e114749
    Description: Accurate and reproducible quantification of the accumulation of proteins into foci in cells is essential for data interpretation and for biological inferences. To improve reproducibility, much emphasis has been placed on the preparation of samples, but less attention has been given to reporting and standardizing the quantification of foci. The current standard to quantitate foci in open-source software is to manually determine a range of parameters based on the outcome of one or a few representative images and then apply the parameter combination to the analysis of a larger dataset. Here, we demonstrate the power and utility of using machine learning to train a new algorithm (FindFoci) to determine optimal parameters. FindFoci closely matches human assignments and allows rapid automated exploration of parameter space. Thus, individuals can train the algorithm to mirror their own assignments and then automate focus counting using the same parameters across a large number of images. Using the training algorithm to match human assignments of foci, we demonstrate that applying an optimal parameter combination from a single image is not broadly applicable to analysis of other images scored by the same experimenter or by other experimenters. Our analysis thus reveals wide variation in human assignment of foci and their quantification. To overcome this, we developed training on multiple images, which reduces the inconsistency of using a single or a few images to set parameters for focus detection. FindFoci is provided as an open-source plugin for ImageJ.
    Subject(s): Algorithms ; Analysis ; Artificial intelligence ; Automation ; Biology and Life Sciences ; Data analysis ; Data interpretation ; Deoxyribonucleic acid ; DNA ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Freeware ; Fungal Proteins - analysis ; Fungal Proteins - metabolism ; Genomes ; Human error ; Humans ; Image detection ; Image Processing, Computer-Assisted ; Learning algorithms ; Life sciences ; Localization ; Machine learning ; Parameters ; Proteins ; Proteins - analysis ; Proteins - metabolism ; Public software ; Reproducibility ; Reproducibility of Results ; Research and Analysis Methods ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Software ; Source code ; Training ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 5
    Language: English
    In: DNA repair, 2018-11, Vol.71, p.135-147
    Description: Flaws in the DNA replication process have emerged as a leading driver of genome instability in human diseases. Alteration to replication fork progression is a defining feature of replication stress and the consequent failure to maintain fork integrity and complete genome duplication within a single round of S-phase compromises genetic integrity. This includes increased mutation rates, small and large scale genomic rearrangement and deleterious consequences for the subsequent mitosis that result in the transmission of additional DNA damage to the daughter cells. Therefore, preserving fork integrity and replication competence is an important aspect of how cells respond to replication stress and avoid genetic change. Homologous recombination is a pivotal pathway in the maintenance of genome integrity in the face of replication stress. Here we review our recent understanding of the mechanisms by which homologous recombination acts to protect, restart and repair replication forks. We discuss the dynamics of these genetically distinct functions and their contribution to faithful mitoticsegregation.
    Subject(s): Biochemistry, Molecular Biology ; Biotechnology ; Cellular Biology ; DNA replication ; Fork integrity ; Fork restart ; Genome instability ; Genomics ; Life Sciences ; Recombination ; Replication stress
    ISSN: 1568-7864
    E-ISSN: 1568-7856
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Nature (London), 2013-01-10, Vol.493 (7431), p.246-249
    Description: Impediments to DNA replication are known to induce gross chromosomal rearrangements (GCRs) and copy-number variations (CNVs). GCRs and CNVs underlie human genomic disorders and are a feature of cancer. During cancer development, environmental factors and oncogene-driven proliferation promote replication stress. Resulting GCRs and CNVs are proposed to contribute to cancer development and therapy resistance. When stress arrests replication, the replisome remains associated with the fork DNA (stalled fork) and is protected by the inter-S-phase checkpoint. Stalled forks efficiently resume when the stress is relieved. However, if the polymerases dissociate from the fork (fork collapse) or the fork structure breaks (broken fork), replication restart can proceed either by homologous recombination or microhomology-primed re-initiation. Here we ascertain the consequences of replication with a fork restarted by homologous recombination in fission yeast. We identify a new mechanism of chromosomal rearrangement through the observation that recombination-restarted forks have a considerably high propensity to execute a U-turn at small inverted repeats (up to 1 in 40 replication events). We propose that the error-prone nature of restarted forks contributes to the generation of GCRs and gene amplification in cancer, and to non-recurrent CNVs in genomic disorders.
    Subject(s): Chromosome Inversion - genetics ; DNA Copy Number Variations - genetics ; DNA replication ; DNA Replication - genetics ; DNA, Fungal - genetics ; DNA, Ribosomal - genetics ; Genes, Fungal - genetics ; Genetic recombination ; Inverted Repeat Sequences - genetics ; Models, Genetic ; Neoplasms - genetics ; Physiological aspects ; Recombination, Genetic - genetics ; Saccharomyces cerevisiae - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 7
    Language: English
    In: Cell, 2012-06-08, Vol.149 (6), p.1221-1232
    Description: When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1Chk2 effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression—regressed leading or lagging strands—on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress. [Display omitted] ► S phase checkpoint deficiency causes reversal of stalled replication forks ► Dna2 prevents fork reversal ► S phase checkpoint targets Dna2 to prevent fork reversal ► Dna2 nuclease activity is essential for stabilizing stalled replication forks The checkpoint kinase Cds1Chk2 regulates the nuclease activity of DNA2 at stalled replication forks to prevent fork reversal
    Subject(s): Analysis ; Checkpoint Kinase 2 ; Chromatin ; DNA Replication ; Epistasis, Genetic ; Flap Endonucleases - metabolism ; Genetically modified organisms ; Genomic Instability ; Phosphorylation ; Protein-Serine-Threonine Kinases - metabolism ; S Phase Cell Cycle Checkpoints ; Schizosaccharomyces - cytology ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 0092-8674
    E-ISSN: 1097-4172
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
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  • 8
    Language: English
    In: Nature communications, 2021-06-22, Vol.12 (1), p.3856-3856
    Description: AbstractThe MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 and Nbs1/Xrs2) initiates double-stranded DNA break repair and activates the Tel1/ATM kinase in the DNA damage response. Telomeres counter both outcomes at chromosome ends, partly by keeping MRN-ATM in check. We show that MRX is disabled by telomeric protein Rif2 through an N-terminal motif (MIN, MRN/X-inhibitory motif). MIN executes suppression of Tel1, DNA end-resection and non-homologous end joining by binding the Rad50 N-terminal region. Our data suggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation, highlighting an Achilles’ heel in MRN, which we propose is also exploited by the RIF2 paralog ORC4 (Origin Recognition Complex 4) in Kluyveromyces lactis and the Schizosaccharomyces pombe telomeric factor Taz1, which is evolutionarily unrelated to Orc4/Rif2. This raises the possibility that analogous mechanisms might be deployed in other eukaryotes as well.
    Subject(s): Chromosomes ; Damage ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Endonuclease ; Eukaryotes ; Homology ; Kinases ; MRE11 protein ; N-Terminus ; Non-homologous end joining ; Origin recognition complex ; Proteins ; Repair ; Telomeres ; Tethering ; Yeast ; Yeasts
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: Chromosoma, 2013-02-28, Vol.122 (1-2), p.33-45
    Description: Maintaining genome stability is essential for the accurate transmission of genetic material. Genetic instability is associated with human genome disorders and is a near-universal hallmark of cancer cells. Genetic variation is also the driving force of evolution, and a genome must therefore display adequate plasticity to evolve while remaining sufficiently stable to prevent mutations and chromosome rearrangements leading to a fitness disadvantage. A primary source of genome instability are errors that occur during chromosome replication. More specifically, obstacles to the movement of replication forks are known to underlie many of the gross chromosomal rearrangements seen both in human cells and in model organisms. Obstacles to replication fork progression destabilize the replisome (replication protein complex) and impact on the integrity of forked DNA structures. Therefore, to ensure the successful progression of a replication fork along with its associated replisome, several distinct strategies have evolved. First, there are well-orchestrated mechanisms that promote continued movement of forks through potential obstacles. Second, dedicated replisome and fork DNA stabilization pathways prevent the dysfunction of the replisome if its progress is halted. Third, should stabilisation fail, there are mechanisms to ensure damaged forks are accurately fused with a converging fork or, when necessary, re-associated with the replication proteins to continue replication. Here, we review what is known about potential barriers to replication fork progression, how these are tolerated and their impact on genome instability.
    Subject(s): Analysis ; Animal Genetics and Genomics ; Biochemistry ; Biochemistry, Molecular Biology ; Biomedical and Life Sciences ; Cell Biology ; Cells ; Chromosome Aberrations ; Chromosome replication ; Developmental Biology ; DNA Repair - genetics ; DNA Replication - genetics ; Eukaryotic Microbiology ; general ; Genome, Human ; Genomic Instability ; Genomics ; Human Genetics ; Humans ; Life Sciences ; Mutation ; Proteins ; Review Article
    ISSN: 0009-5915
    E-ISSN: 1432-0886
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: Nature communications, 2016-04-21, Vol.7 (1), p.11364-11
    Description: Double-strand breaks repaired by homologous recombination (HR) are first resected to form single-stranded DNA, which binds replication protein A (RPA). RPA attracts mediators that load the Rad51 filament to promote strand invasion, the defining feature of HR. How the resection machinery navigates nucleosome-packaged DNA is poorly understood. Here we report that in Schizosaccharomyces pombe a conserved DDB1-CUL4-associated factor (DCAF), Wdr70, is recruited to DSBs as part of the Cullin4-DDB1 ubiquitin ligase (CRL4 Wdr70 ) and stimulates distal H2B lysine 119 mono-ubiquitination (uH2B). Wdr70 deletion, or uH2B loss, results in increased loading of the checkpoint adaptor and resection inhibitor Crb253BP1 , decreased Exo1 association and delayed resection. Wdr70 is dispensable for resection upon Crb253BP1 loss, or when the Set9 methyltransferase that creates docking sites for Crb2 is deleted. Finally, we establish that this histone regulatory cascade similarly controls DSB resection in human cells.
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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