Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity
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{"title"=>"Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity", "type"=>"journal", "authors"=>[{"first_name"=>"Robert J.", "last_name"=>"Buckland", "scopus_author_id"=>"55816614200"}, {"first_name"=>"Danielle L.", "last_name"=>"Watt", "scopus_author_id"=>"7202774362"}, {"first_name"=>"Balasubramanyam", "last_name"=>"Chittoor", "scopus_author_id"=>"36056106200"}, {"first_name"=>"Anna Karin", "last_name"=>"Nilsson", "scopus_author_id"=>"36342730900"}, {"first_name"=>"Thomas A.", "last_name"=>"Kunkel", "scopus_author_id"=>"7102904982"}, {"first_name"=>"Andrei", "last_name"=>"Chabes", "scopus_author_id"=>"6701827550"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84919684017", "pui"=>"601033572", "pmid"=>"25474551", "issn"=>"15537404", "doi"=>"10.1371/journal.pgen.1004846", "sgr"=>"84919684017"}, "id"=>"81777c45-be50-30ba-8871-81766c96f422", "abstract"=>"The fidelity of DNA replication requires an appropriate balance of dNTPs, yet the nascent leading and lagging strands of the nuclear genome are primarily synthesized by replicases that differ in subunit composition, protein partnerships and biochemical properties, including fidelity. These facts pose the question of whether imbalanced dNTP pools differentially influence leading and lagging strand replication fidelity. Here we test this possibility by examining strand-specific replication infidelity driven by a mutation in yeast ribonucleotide reductase, rnr1-Y285A, that leads to elevated dTTP and dCTP concentrations. The results for the CAN1 mutational reporter gene present in opposite orientations in the genome reveal that the rates, and surprisingly even the sequence contexts, of replication errors are remarkably similar for leading and lagging strand synthesis. Moreover, while many mismatches driven by the dNTP pool imbalance are efficiently corrected by mismatch repair, others are repaired less efficiently, especially those in sequence contexts suggesting reduced proofreading due to increased mismatch extension driven by the high dTTP and dCTP concentrations. Thus the two DNA strands of the nuclear genome are at similar risk of mutations resulting from this dNTP pool imbalance, and this risk is not completely suppressed even when both major replication error correction mechanisms are genetically intact.", "link"=>"http://www.mendeley.com/research/increased-imbalanced-dntp-pools-symmetrically-promote-both-leading-lagging-strand-replication-infide", "reader_count"=>34, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>3, "Student > Master"=>5, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>3, "Student > Master"=>5, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>2, "Physics and Astronomy"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Physics and Astronomy"=>{"Physics and Astronomy"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}}, "reader_count_by_country"=>{"Korea (South)"=>1, "Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1822543"], "description"=>"<p>Numbers above columns show the factor increase over wt. Error bars show Standard Error of Mean.</p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260850, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_dNTP_pools_of_the_strains_with_the_imbalanced_dNTP_pools_/1260850", "title"=>"dNTP pools of the strains with the imbalanced dNTP pools.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822545"], "description"=>"<p>Mutations rates by class.</p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260852, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutations_rates_by_class_/1260852", "title"=>"Mutations rates by class.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822548"], "description"=>"<p>A. Cartoon representation of <i>CAN1</i><b> orientation in </b><i>rnr1-Y285A</i><b> strains.</b> B. Model showing strand assignment in the two <i>rnr1-Y285A</i> mutants (OR1 and OR2) using the hotspot at site 648 bp as an example. MI =  Misinsertion. Red characters represent the mutational event and green characters represent bases where the dNTP is at an excessively high concentration.</p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260855, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Strand_Assignment_Model_/1260855", "title"=>"Strand Assignment Model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822549"], "description"=>"<p>Symbols indicate the following: plus - additions, triangles - deletions, squares - transversions, circles - transitions, red - occur during leading strand synthesis, blue - occur during lagging strand synthesis, black - mutation cannot be assigned to a strand. <sup>a</sup> Reanalysed from the dataset published in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004846#pgen.1004846-Kumar2\" target=\"_blank\">[17]</a>.</p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260856, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simplified_CAN1_mutation_spectra_showing_hotpots_where_mutation_rate_is_greater_than_10_fold_that_in_wt_for_rnr1_Y285A_CAN1_OR1_n_173_rnr1_Y285A_CAN1_OR2_n_170_rnr1_Y285A_msh2_n_259_and_msh2_n_164_where_n_number_of_individual_colonies_sequenced_/1260856", "title"=>"Simplified <i>CAN1</i> mutation spectra showing hotpots (where mutation rate is greater than 10-fold that in wt) for <i>rnr1-Y285A CAN1-OR1</i> (n = 173), <i>rnr1-Y285A CAN1-OR2</i> (n = 170), <i>rnr1-Y285A msh2</i>Δ (n = 259), and <i>msh2</i>Δ (n = 164) where n =  number of individual colonies sequenced.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822552"], "description"=>"<p></p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260859, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_CAN1_mutation_rates_at_hotspots_predominant_mutation_at_site_in_rnr1_Y285A_strains_with_natural_OR1_and_reversed_OR2_orientation_of_the_CAN1_gene_/1260859", "title"=>"Comparison of <i>CAN1</i> mutation rates at hotspots (predominant mutation at site) in <i>rnr1-Y285A</i> strains with natural (OR1) and reversed (OR2) orientation of the <i>CAN1</i> gene.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822554"], "description"=>"<p>A. Comparison of site mutation rates at major hotspots in <i>rnr1-Y285A</i><b> with (left axis) and without MMR (right axis).</b> B. MMR correction factor at these sites in the presence of an <i>rnr1-Y285A</i> dNTP pool imbalance. </p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260860, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mismatch_repair_efficiency_/1260860", "title"=>"Mismatch repair efficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822555"], "description"=>"<p>Data previously published in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004846#pgen.1004846-Kumar2\" target=\"_blank\">[17]</a>.</p><p><i>CAN1</i> mutation rates and observed events.<sup>a</sup></p>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260861, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CAN1_mutation_rates_and_observed_events_a_/1260861", "title"=>"<i>CAN1</i> mutation rates and observed events.<sup>a</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-04 03:27:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1822602", "https://ndownloader.figshare.com/files/1822603", "https://ndownloader.figshare.com/files/1822605", "https://ndownloader.figshare.com/files/1822606", "https://ndownloader.figshare.com/files/1822607", "https://ndownloader.figshare.com/files/1822608"], "description"=>"<div><p>The fidelity of DNA replication requires an appropriate balance of dNTPs, yet the nascent leading and lagging strands of the nuclear genome are primarily synthesized by replicases that differ in subunit composition, protein partnerships and biochemical properties, including fidelity. These facts pose the question of whether imbalanced dNTP pools differentially influence leading and lagging strand replication fidelity. Here we test this possibility by examining strand-specific replication infidelity driven by a mutation in yeast ribonucleotide reductase, <i>rnr1-Y285A</i>, that leads to elevated dTTP and dCTP concentrations. The results for the <i>CAN1</i> mutational reporter gene present in opposite orientations in the genome reveal that the rates, and surprisingly even the sequence contexts, of replication errors are remarkably similar for leading and lagging strand synthesis. Moreover, while many mismatches driven by the dNTP pool imbalance are efficiently corrected by mismatch repair, others are repaired less efficiently, especially those in sequence contexts suggesting reduced proofreading due to increased mismatch extension driven by the high dTTP and dCTP concentrations. Thus the two DNA strands of the nuclear genome are at similar risk of mutations resulting from this dNTP pool imbalance, and this risk is not completely suppressed even when both major replication error correction mechanisms are genetically intact.</p></div>", "links"=>[], "tags"=>["dNTP pool imbalance", "Lagging Strand Replication Infidelity", "genome", "sequence contexts", "mutation", "Imbalanced dNTP Pools Symmetrically Promote", "dna", "mismatch", "replication error correction mechanisms", "dttp", "dCTP concentrations", "yeast ribonucleotide reductase", "imbalanced dNTP pools differentially influence", "strand replication fidelity"], "article_id"=>1260888, "categories"=>["Uncategorised"], "users"=>["Robert J. Buckland", "Danielle L. Watt", "Balasubramanyam Chittoor", "Anna Karin Nilsson", "Thomas A. Kunkel", "Andrei Chabes"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004846.s001", "https://dx.doi.org/10.1371/journal.pgen.1004846.s002", "https://dx.doi.org/10.1371/journal.pgen.1004846.s003", "https://dx.doi.org/10.1371/journal.pgen.1004846.s004", "https://dx.doi.org/10.1371/journal.pgen.1004846.s005", "https://dx.doi.org/10.1371/journal.pgen.1004846.s006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_and_Imbalanced_dNTP_Pools_Symmetrically_Promote_Both_Leading_and_Lagging_Strand_Replication_Infidelity_/1260888", "title"=>"Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-12-04 03:27:38"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[282]}, {"subject_area"=>"/Biology and life sciences/Evolutionary biology", "average_usage"=>[333]}, {"subject_area"=>"/Biology and life sciences/Population biology", "average_usage"=>[312, 475]}]}
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