Design Principles of the Yeast G1/S Switch
Publication Date
October 01, 2013
Journal
PLOS Biology
Authors
Xiaojing Yang, Kai Yeung Lau, Volkan Sevim & Chao Tang
Volume
11
Issue
10
Pages
e1001673
DOI
https://dx.plos.org/10.1371/journal.pbio.1001673
Publisher URL
http://journals.plos.org/plosbiology/article?id=10.1371%2Fjournal.pbio.1001673
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24130459
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794861
Europe PMC
http://europepmc.org/abstract/MED/24130459
Web of Science
000330350700005
Scopus
84886620259
Mendeley
http://www.mendeley.com/research/design-principles-yeast-g1s-switch
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Mendeley | Further Information

{"title"=>"Design Principles of the Yeast G1/S Switch", "type"=>"journal", "authors"=>[{"first_name"=>"Xiaojing", "last_name"=>"Yang", "scopus_author_id"=>"55811928600"}, {"first_name"=>"Kai Yeung", "last_name"=>"Lau", "scopus_author_id"=>"55906065200"}, {"first_name"=>"Volkan", "last_name"=>"Sevim", "scopus_author_id"=>"8876478600"}, {"first_name"=>"Chao", "last_name"=>"Tang", "scopus_author_id"=>"7404393967"}], "year"=>2013, "source"=>"PLoS Biology", "identifiers"=>{"doi"=>"10.1371/journal.pbio.1001673", "sgr"=>"84886620259", "issn"=>"15449173", "pui"=>"370141428", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)", "pmid"=>"24130459", "scopus"=>"2-s2.0-84886620259"}, "id"=>"1726113d-5803-3d60-96a7-96c002d97896", "abstract"=>"A hallmark of the G1/S transition in budding yeast cell cycle is the proteolytic degradation of the B-type cyclin-Cdk stoichiometric inhibitor Sic1. Deleting SIC1 or altering Sic1 degradation dynamics increases genomic instability. Certain key facts about the parts of the G1/S circuitry are established: phosphorylation of Sic1 on multiple sites is necessary for its destruction, and both the upstream kinase Cln1/2-Cdk1 and the downstream kinase Clb5/6-Cdk1 can phosphorylate Sic1 in vitro with varied specificity, cooperativity, and processivity. However, how the system works as a whole is still controversial due to discrepancies between in vitro, in vivo, and theoretical studies. Here, by monitoring Sic1 destruction in real time in individual cells under various perturbations to the system, we provide a clear picture of how the circuitry functions as a switch in vivo. We show that Cln1/2-Cdk1 sets the proper timing of Sic1 destruction, but does not contribute to its destruction speed; thus, it acts only as a trigger. Sic1's inhibition target Clb5/6-Cdk1 controls the speed of Sic1 destruction through a double-negative feedback loop, ensuring a robust all-or-none transition for Clb5/6-Cdk1 activity. Furthermore, we demonstrate that the degradation of a single-phosphosite mutant of Sic1 is rapid and switch-like, just as the wild-type form. Our mathematical model confirms our understanding of the circuit and demonstrates that the substrate sharing between the two kinases is not a redundancy but a part of the design to overcome the trade-off between the timing and sharpness of Sic1 degradation. Our study provides direct mechanistic insight into the design features underlying the yeast G1/S switch.", "link"=>"http://www.mendeley.com/research/design-principles-yeast-g1s-switch", "reader_count"=>68, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>5, "Researcher"=>9, "Student > Ph. D. Student"=>29, "Student > Master"=>8, "Other"=>2, "Student > Bachelor"=>7, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>5, "Researcher"=>9, "Student > Ph. D. Student"=>29, "Student > Master"=>8, "Other"=>2, "Student > Bachelor"=>7, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>11, "Agricultural and Biological Sciences"=>45, "Physics and Astronomy"=>4, "Chemistry"=>2, "Social Sciences"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>45}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "Germany"=>2}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1221740"], "description"=>"<p>(A) The topology of the network. The parts encircled by the blue and red rectangles are topologically two feedback loops. (B) Combined phase and fluorescence time-course images in wild-type cells (green, the endogenous Sic1; red, histone marker for the nucleus). (C) A sample Sic1-GFP time course used to extract half-life. The leftmost panel is a linear plot for wild-type, with the blue line being a fit to the exponential function <i>a</i>exp(−<i>bt</i>)+<i>c</i>. The three right panels are semi-log plots, with the red line being a fit to ln(<i>a</i>)−<i>bt</i>. (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673.s014\" target=\"_blank\">Text S1</a> for details) (D) Sic1 single cell profile samples. The profiles are aligned at the time point of the maximum Sic1 concentration (time interval, 1 min). (E) Average Sic1 profiles for the three strains indicated (the same alignment as in E). (F) Sic1 half-life for wild-type and various deletion strains. (G) Simulation results from a stochastic model of the system. Each data point corresponds to a different realization (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673.s015\" target=\"_blank\">Text S2</a> for details).</p>", "links"=>[], "tags"=>["sic1", "controlled"], "article_id"=>812544, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g002", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_speed_of_Sic1_destruction_in_vivo_is_controlled_by_Clb5_6_Cdk1_/812544", "title"=>"The speed of Sic1 destruction <i>in vivo</i> is controlled by Clb5/6-Cdk1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221738"], "description"=>"<p>Black lines represent the current understanding; the role of the red line is discussed in the article.</p>", "links"=>[], "tags"=>["molecular", "controlling", "budding"], "article_id"=>812542, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g001", "stats"=>{"downloads"=>5, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_molecular_network_controlling_the_G1_S_transition_in_budding_yeast_/812542", "title"=>"The molecular network controlling the G1/S transition in budding yeast.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221747"], "description"=>"<p>(A) The new model of the G1/S transition. (B) The switch motif at the various transitions in cell-cycle regulation.</p>", "links"=>[], "tags"=>["motif", "biochemical"], "article_id"=>812551, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g007", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_common_motif_of_biochemical_switch_/812551", "title"=>"A common motif of biochemical switch.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221743"], "description"=>"<p>(A) The topology of the G1/S switch. Colored nodes and link are perturbed to assess their role in the timing of Sic1 destruction, as shown in the following panels. (B) Combined phase and fluorescence time-course images in wild-type cells (red, the endogenous Whi5-mCherry; green, the endogenous Sic1-GFP). White arrows indicate the time where Whi5 is being excluded out of nucleus and Sic1 is being degraded, in a mother and a daughter cell, respectively. (C) The construction of the Cln2 binding site mutant of Sic1. (D) Typical Sic1 profiles in various strains. The profiles are aligned at the point of Whi5 nuclear exit (t = 0). (E and F) The initiation time of Sic1 degradation (E) and the Sic1 half-life (F) in wild-type, Cln2 binding site Sic1 mutant, <i>cln1Δcln2Δ</i>, and <i>clb5Δclb6Δ</i> strains. (G) The average of Sic1 profiles from all single cells, aligned at Whi5 nuclear exit.</p>", "links"=>[], "tags"=>["sets", "sic1"], "article_id"=>812547, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g004", "stats"=>{"downloads"=>4, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cln1_2_Cdk1_sets_the_proper_timing_of_Sic1_destruction_/812547", "title"=>"Cln1/2-Cdk1 sets the proper timing of Sic1 destruction.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221765", "https://ndownloader.figshare.com/files/1221766", "https://ndownloader.figshare.com/files/1221767", "https://ndownloader.figshare.com/files/1221768", "https://ndownloader.figshare.com/files/1221769", "https://ndownloader.figshare.com/files/1221770", "https://ndownloader.figshare.com/files/1221771", "https://ndownloader.figshare.com/files/1221772", "https://ndownloader.figshare.com/files/1221773", "https://ndownloader.figshare.com/files/1221774", "https://ndownloader.figshare.com/files/1221775", "https://ndownloader.figshare.com/files/1221776", "https://ndownloader.figshare.com/files/1221777", "https://ndownloader.figshare.com/files/1221778", "https://ndownloader.figshare.com/files/1221779", "https://ndownloader.figshare.com/files/1221780"], "description"=>"<div><p>A hallmark of the G1/S transition in budding yeast cell cycle is the proteolytic degradation of the B-type cyclin-Cdk stoichiometric inhibitor Sic1. Deleting <i>SIC1</i> or altering Sic1 degradation dynamics increases genomic instability. Certain key facts about the parts of the G1/S circuitry are established: phosphorylation of Sic1 on multiple sites is necessary for its destruction, and both the upstream kinase Cln1/2-Cdk1 and the downstream kinase Clb5/6-Cdk1 can phosphorylate Sic1 <i>in vitro</i> with varied specificity, cooperativity, and processivity. However, how the system works as a whole is still controversial due to discrepancies between <i>in vitro</i>, <i>in vivo</i>, and theoretical studies. Here, by monitoring Sic1 destruction in real time in individual cells under various perturbations to the system, we provide a clear picture of how the circuitry functions as a switch <i>in vivo</i>. We show that Cln1/2-Cdk1 sets the proper timing of Sic1 destruction, but does not contribute to its destruction speed; thus, it acts only as a trigger. Sic1's inhibition target Clb5/6-Cdk1 controls the speed of Sic1 destruction through a double-negative feedback loop, ensuring a robust all-or-none transition for Clb5/6-Cdk1 activity. Furthermore, we demonstrate that the degradation of a single-phosphosite mutant of Sic1 is rapid and switch-like, just as the wild-type form. Our mathematical model confirms our understanding of the circuit and demonstrates that the substrate sharing between the two kinases is not a redundancy but a part of the design to overcome the trade-off between the timing and sharpness of Sic1 degradation. Our study provides direct mechanistic insight into the design features underlying the yeast G1/S switch.</p></div>", "links"=>[], "tags"=>["principles", "yeast"], "article_id"=>812561, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1001673.s001", "https://dx.doi.org/10.1371/journal.pbio.1001673.s002", "https://dx.doi.org/10.1371/journal.pbio.1001673.s003", "https://dx.doi.org/10.1371/journal.pbio.1001673.s004", "https://dx.doi.org/10.1371/journal.pbio.1001673.s005", "https://dx.doi.org/10.1371/journal.pbio.1001673.s006", "https://dx.doi.org/10.1371/journal.pbio.1001673.s007", "https://dx.doi.org/10.1371/journal.pbio.1001673.s008", "https://dx.doi.org/10.1371/journal.pbio.1001673.s009", "https://dx.doi.org/10.1371/journal.pbio.1001673.s010", "https://dx.doi.org/10.1371/journal.pbio.1001673.s011", "https://dx.doi.org/10.1371/journal.pbio.1001673.s012", "https://dx.doi.org/10.1371/journal.pbio.1001673.s013", "https://dx.doi.org/10.1371/journal.pbio.1001673.s014", "https://dx.doi.org/10.1371/journal.pbio.1001673.s015", "https://dx.doi.org/10.1371/journal.pbio.1001673.s016"], "stats"=>{"downloads"=>36, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Design_Principles_of_the_Yeast_G1_S_Switch_/812561", "title"=>"Design Principles of the Yeast G1/S Switch", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221742"], "description"=>"<p>(A) Black lines, the topology of the G1/S switch. Grey lines, interaction of the reporter Sic1* with the circuit. Sic1* “reports” the destruction dynamics of Sic1. Perturbations to the DNFBL are indicated by the colored crosses. (B) The construction of the reporter Sic1*. (C) Sic1* has the same subcellular localization and the same degradation dynamics as the endogenous Sic1. Shown in the figure is fluorescence time course images of the reporter Sic1*(red) and the endogenous Sic1 (green). (D–F) Sic1* half-life with the DNFBL intact (black dots) and perturbed (colored dots). (D) The DNFBL was perturbed by deleting <i>SIC1</i>. The cells were further subjected to genetic perturbations as indicated below the data points. (E) The DNFBL was perturbed by deleting <i>SIC1</i>. The cells were further subjected to environmental perturbations as indicated below the data points. (F) The DNFBL was perturbed by deleting the link between Clb5/6-Cdk1 and Sic1, which was accomplished by using the nonphosphorylatable Sic1-0p <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673-Cross1\" target=\"_blank\">[44]</a>. The cells were further subjected to environmental perturbations as indicated below the data points. (G–H) The activity of <i>CLN2</i> and <i>CLB5</i> promoter under various genetic perturbations (G) and environmental stress (H). Each grey line is from an unstressed cell; each colored line is from a stressed cell. Thick dashed lines are averages of the two groups, respectively. The lines were smoothed for clarity.</p>", "links"=>[], "tags"=>["double-negative", "sic1", "ensures", "robustness"], "article_id"=>812546, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g003", "stats"=>{"downloads"=>3, "page_views"=>47, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_double_negative_feedback_loop_DNFBL_between_Sic1_and_Clb5_6_Cdk1_ensures_robustness_in_Sic1_destruction_speed_/812546", "title"=>"The double-negative feedback loop (DNFBL) between Sic1 and Clb5/6-Cdk1 ensures robustness in Sic1 destruction speed.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221745"], "description"=>"<p>(A) The mathematical model of the switch illustrated. Small circles on Inhibitor represent phosphorylation sites, and the red and blue shaded areas on each circle represent the magnitudes of catalytic efficiencies of each kinase for that site, schematically. Inhibitor sequesters Kinase2. (B) Definitions of timing and sharpness illustrated on a sample run (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673.s016\" target=\"_blank\">Text S3</a> for details). (C) <i>In silico</i> evolution to optimize the catalytic efficiencies of the kinases for a desired function in discrete steps of mutation and selection (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673.s005\" target=\"_blank\">Figure S5A</a> for a detailed illustration). (D) The double-negative feedback and the linear circuit were optimized for sharpness of Kinase2 activation. Distributions for Inhibitor half-life and activation timing after optimization are shown on the right. (E) An upstream trigger is added to the double-negative feedback circuit that is already optimized for sharpness. The circuit is then optimized for timing by mutating the catalytic efficiency of Kinase1 only. The resulting circuit greatly reduced the timing variability, but also slightly decreased sharpness. (F) Dynamical behavior of each design is shown using the data from (D) and (E). Linear circuit produces consistent timing, but variable sharpness; double-negative feedback produces consistent sharpness, but variable timing. Collaboration of two kinases leads to robustness in both timing and sharpness in Kinase2 activation (see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001673#pbio.1001673.s005\" target=\"_blank\">Figure S5C</a> for a more detailed illustration). (G) The trade-off between timing and sharpness shown in a double-negative feedback loop with various levels of Inhibitor.</p>", "links"=>[], "tags"=>["optimization", "circuits", "functions", "further", "reveals"], "article_id"=>812549, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g006", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Computational_optimization_of_the_circuits_for_specific_functions_further_reveals_general_design_principles_/812549", "title"=>"Computational optimization of the circuits for specific functions further reveals general design principles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1221744"], "description"=>"<p>(A) The construction of the Sic1<sup>CPD</sup> mutant. (B) Example time course of Sic1-GFP (left) and Sic1<sup>CPD</sup>-GFP (right). Different colors represent different cells. Two mother cells (solid lines) and two daughter cells (dashed lines) are shown. The insets show higher time-resolution (1 frame/min) from a typical cell and fit to exponential decay, along with the fitted half-life. (C) Sic1 half-life and Sic1<sup>CPD</sup> half-life. Each dot represents a measurement of a single cell. (D) Timing for wild-type and SIC1<sup>CPD</sup> strains, respectively. Each dot represents a measurement of a single cell. (E) Sic1 and Sic1<sup>CPD</sup> profile averages over all cells. Single-cell profiles are aligned at t = 0 (Whi5 nuclear exit) for averaging.</p>", "links"=>[], "tags"=>["multisite", "phosphorylation"], "article_id"=>812548, "categories"=>["Biological Sciences"], "users"=>["Xiaojing Yang", "Kai-Yeung Lau", "Volkan Sevim", "Chao Tang"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001673.g005", "stats"=>{"downloads"=>5, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_multisite_phosphorylation_scheme_is_not_required_for_fast_destruction_of_Sic1_/812548", "title"=>"A multisite phosphorylation scheme is not required for fast destruction of Sic1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-01 02:44:03"}

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Relative Metric

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