A Yeast GSK-3 Kinase Mck1 Promotes Cdc6 Degradation to Inhibit DNA Re-Replication
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{"title"=>"A Yeast GSK-3 Kinase Mck1 Promotes Cdc6 Degradation to Inhibit DNA Re-Replication", "type"=>"journal", "authors"=>[{"first_name"=>"Amy E.", "last_name"=>"Ikui", "scopus_author_id"=>"6701614891"}, {"first_name"=>"Valentina", "last_name"=>"Rossio", "scopus_author_id"=>"35081130200"}, {"first_name"=>"Lea", "last_name"=>"Schroeder", "scopus_author_id"=>"7102059866"}, {"first_name"=>"Satoshi", "last_name"=>"Yoshida", "scopus_author_id"=>"55980548500"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84872020666", "pmid"=>"23236290", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pui"=>"368067375", "issn"=>"15537390", "scopus"=>"2-s2.0-84872020666", "doi"=>"10.1371/journal.pgen.1003099"}, "id"=>"c9b1e23e-79c3-3177-b6fc-f3f2ec93d884", "abstract"=>"Cdc6p is an essential component of the pre-replicative complex (pre-RC), which binds to DNA replication origins to promote initiation of DNA replication. Only once per cell cycle does DNA replication take place. After initiation, the pre-RC components are disassembled in order to prevent re-replication. It has been shown that the N-terminal region of Cdc6p is targeted for degradation after phosphorylation by Cyclin Dependent Kinase (CDK). Here we show that Mck1p, a yeast homologue of GSK-3 kinase, is also required for Cdc6 degradation through a distinct mechanism. Cdc6 is an unstable protein and is accumulated in the nucleus only during G1 and early S-phase in wild-type cells. In mck1 deletion cells, CDC6p is stabilized and accumulates in the nucleus even in late S phase and mitosis. Overexpression of Mck1p induces rapid Cdc6p degradation in a manner dependent on Threonine-368, a GSK-3 phosphorylation consensus site, and SCF(CDC4). We show evidence that Mck1p-dependent degradation of Cdc6 is required for prevention of DNA re-replication. Loss of Mck1 activity results in synthetic lethality with other pre-RC mutants previously implicated in re-replication control, and these double mutant strains over-replicate DNA within a single cell cycle. These results suggest that a GSK3 family protein plays an unexpected role in preventing DNA over-replication through Cdc6 degradation in Saccharomyces cerevisiae. We propose that both CDK and Mck1 kinases are required for Cdc6 degradation to ensure a tight control of DNA replication.", "link"=>"http://www.mendeley.com/research/yeast-gsk3-kinase-mck1-promotes-cdc6-degradation-inhibit-dna-rereplication", "reader_count"=>32, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>5, "Student > Master"=>4, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>5, "Student > Master"=>4, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>8, "Agricultural and Biological Sciences"=>21, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>21}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/530349"], "description"=>"<p>(A) First, the <i>Δmck1 GALL-MCK1 CDC6-prA</i> cells were incubated in glucose plus nocodazole in order to arrest the cell cycle during mitosis. Then, the nocodazole was removed and the media was switched to either glucose or galactose. Samples were taken every 10 minutes, proteins were extracted and subjected to western blotting as described above. Control experiments were performed using <i>Δmck1 CDC6-prA</i> cells to show that galactose does not affect Cdc6 level. Pgk1 was used as a loading control. (B) <i>cdc4-1 CDC6-prA Δmck1 GALL-MCK1</i> strain was incubated in raffinose-containing media first. The cell cycle was blocked by nocodazole and then the cells were further incubated either at 26°C or 36°C for 1.5 hours. Galactose was added to the media, samples were collected every 10 minutes and the protein extracts were subjected to western blotting to detect Cdc6-prA. Pgk1 was used as a loading control.</p>", "links"=>[], "tags"=>["degradation", "cdc6p", "mck1p", "overexpression", "was", "inhibited"], "article_id"=>200836, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g005", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rapid_degradation_of_Cdc6p_by_Mck1p_overexpression_was_inhibited_in_cdc4_mutant_/200836", "title"=>"Rapid degradation of Cdc6p by Mck1p overexpression was inhibited in <i>cdc4</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:13:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/530503"], "description"=>"<p>(A) GSK-3 and CDK consensus sites in the Cdc6 C-terminal region were shown as a red and blue line, respectively. (B) The <i>pRS426</i> (control plasmid), <i>CDC6</i> or <i>CDC6<sup>T368A S372A</sup></i> in 2micron plasmids were transformed into <i>ORC6-WT, ORC6-rxl, ORC6-ps</i> or <i>ORC6-rxl,ps</i> mutants and plated on SD-Ura plates. Transformation efficiency for each strain was shown as CFU/µg DNA. (C) <i>Δmck1 cdc4-1 CDC6-prA</i> cells (labeled as <i>Δmck1</i>) or <i>cdc4-1 CDC6-prA</i> cells (labeled as <i>WT</i>) were arrested during metaphase by nocodazole for 1 hour and then temperature shifted to 37°C for 1.5 hour. Proteins were extracted and subjected to western blotting to detect Cdc6-prA. (D) Protein extracts in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003099#pgen-1003099-g007\" target=\"_blank\">Figure 7C</a> were treated with 10 units of CIP and incubated for 10 minutes at 4 degrees. 20 µl of protein sample from <i>Δmck1</i> cells or 60 µl of protein samples from WT cells were used in order to normalize the Cdc6 protein expression. (E) An extra copy of <i>CDC6</i> or <i>CDC6T368</i>A was integrated into a Δ<i>mck1 GALL-MCK1 CDC6-proteinA</i> strain at the URA locus. The resulting Δ<i>mck1 GALL-MCK1 CDC6-proteinA URA::CDC6T368A</i> cells were treated with nocodazole. Next, the mitotic arrested cells were incubated in YEPG to overexpress Mck1p and supplemented with nocodazole. Cells were collected every 15 minutes. Endogenous Cdc6-proteinA or exogenous Cdc6T368A was analyzed by western blot.</p>", "links"=>[], "tags"=>["gsk-3", "cdc6", "cdc6p"], "article_id"=>201001, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g007", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutations_at_the_GSK_3_consensus_site_in_Cdc6_play_a_role_in_Cdc6p_stability_/201001", "title"=>"Mutations at the GSK-3 consensus site in Cdc6 play a role in Cdc6p stability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:16:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/530127"], "description"=>"<p>(A) Cells with indicated genotypes were plated with a 10-fold dilution on YEPD plates. The plates were incubated at indicated temperatures for 2 days. (B) Asynchronus population cells with indicated genotypes (with wild type <i>MCK1</i> or with <i>mck1-16</i> mutation) were incubated at 26°C first and then shifted to 36°C for 4 hours. Cells were fixed, stained by propidium iodide and analyzed by FACS. Percentage of the cell population over 2C DNA content is shown.</p>", "links"=>[], "tags"=>["dna", "re-replication", "mck1", "kinase"], "article_id"=>200620, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mechanism_of_DNA_re_replication_control_by_Mck1_kinase_is_additive_/200620", "title"=>"Mechanism of DNA re-replication control by Mck1 kinase is additive.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:10:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/530669"], "description"=>"<p>Genetic interaction between <i>mck1</i> deletion and cyclin mutants.</p>", "links"=>[], "tags"=>["deletion", "cyclin"], "article_id"=>201165, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.t001", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_interaction_between_mck1_deletion_and_cyclin_mutants_/201165", "title"=>"Genetic interaction between <i>mck1</i> deletion and cyclin mutants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-06 00:19:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/285793", "https://ndownloader.figshare.com/files/285829", "https://ndownloader.figshare.com/files/285863", "https://ndownloader.figshare.com/files/285910"], "description"=>"<div><p>Cdc6p is an essential component of the pre-replicative complex (pre-RC), which binds to DNA replication origins to promote initiation of DNA replication. Only once per cell cycle does DNA replication take place. After initiation, the pre-RC components are disassembled in order to prevent re-replication. It has been shown that the N-terminal region of Cdc6p is targeted for degradation after phosphorylation by Cyclin Dependent Kinase (CDK). Here we show that Mck1p, a yeast homologue of GSK-3 kinase, is also required for Cdc6 degradation through a distinct mechanism. Cdc6 is an unstable protein and is accumulated in the nucleus only during G1 and early S-phase in wild-type cells. In <em>mck1</em> deletion cells, CDC6p is stabilized and accumulates in the nucleus even in late S phase and mitosis. Overexpression of Mck1p induces rapid Cdc6p degradation in a manner dependent on Threonine-368, a GSK-3 phosphorylation consensus site, and SCF<sup>CDC4</sup>. We show evidence that Mck1p-dependent degradation of Cdc6 is required for prevention of DNA re-replication. Loss of Mck1 activity results in synthetic lethality with other pre-RC mutants previously implicated in re-replication control, and these double mutant strains over-replicate DNA within a single cell cycle. These results suggest that a GSK3 family protein plays an unexpected role in preventing DNA over-replication through Cdc6 degradation in <em>Saccharomyces cerevisiae</em>. We propose that both CDK and Mck1 kinases are required for Cdc6 degradation to ensure a tight control of DNA replication.</p> </div>", "links"=>[], "tags"=>["yeast", "gsk-3", "kinase", "mck1", "promotes", "cdc6", "degradation", "inhibit", "dna", "re-replication"], "article_id"=>116336, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003099.s001", "https://dx.doi.org/10.1371/journal.pgen.1003099.s002", "https://dx.doi.org/10.1371/journal.pgen.1003099.s003", "https://dx.doi.org/10.1371/journal.pgen.1003099.s004"], "stats"=>{"downloads"=>12, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Yeast_GSK_3_Kinase_Mck1_Promotes_Cdc6_Degradation_to_Inhibit_DNA_Re_Replication__/116336", "title"=>"A Yeast GSK-3 Kinase Mck1 Promotes Cdc6 Degradation to Inhibit DNA Re-Replication", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-12-06 01:45:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/530424"], "description"=>"<p>(A) Cdc6 contains eight CDK consensus sites, <sup>S</sup>/<sub>T</sub>P motif indicated by short lines (top). The Cdc6ΔNT mutant lacks the N-terminal region, from amino acid 2–49, thereby lacking the first four CDK sites (bottom). The GSK-3 consensus sites located at 39–43 and 368–372 are indicated by short red lines. (B) Yeast two hybrid analysis was performed to determine the binding site between Mck1p and Cdc6p. A full length <i>MCK1</i> in pACT plasmid, containing the GAL4 activation domain (GAD), was co-transformed into L40 yeast strains along with the various <i>CDC6</i> mutants in the pBTM116 plasmid fused to LexA. Transformants were assayed for β-galactosidase activity as visualized in blue. (C) Co-immunoprecipitation analysis was performed using <i>MCK1-MYC CDC6ΔNT-HA</i>, <i>MCK1-MYC or CDC6ΔNT-HA</i> strain. Cells were incubated in raffinose to log phase and then switched to Galactose to induce <i>GAL-CDC6ΔNT</i>. After 2 hour incubation, nocodazole was added to the media in order to block cell cycle during G2/M. The cells were incubated for two more hours and protein was extracted. The protein lysate from each strain was incubated with agarose beads conjugated with anti-MYC to pull down the Mck1 complex. The protein complex was subjected to western blotting to analyze Mck1-MYC or Cdc6DNT-HA using anti-MYC or anti-HA antibodies, respectively. 1/50 of the original protein lysate was used as INPUT.</p>", "links"=>[], "tags"=>["interacts", "cdc6p", "gsk-3", "c-terminal"], "article_id"=>200915, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g006", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mck1p_interacts_with_Cdc6p_through_the_GSK_3_consensus_site_in_the_C_terminal_region_/200915", "title"=>"Mck1p interacts with Cdc6p through the GSK-3 consensus site in the C-terminal region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:15:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/530199"], "description"=>"<p>(A) <i>GAL-CDC6-HA</i> (WT) or <i>Δmck1 GAL-CDC6-HA</i> (<i>Δmck1</i>) cells were incubated in raffinose first, then transferred to galactose media for 2 hours. Nocodazole was added and the cells were incubated for 2 more hours. Cdc6 expression was suppressed by adding glucose. Samples were collected every 5 minutes. Protein extracts were made and subjected to western blot analysis to observe Cdc6-HA. Pgk1 was used as a loading control. (B) <i>CDC6-prA</i> or <i>Δmck1 CDC6-prA</i> cells were treated with alpha-factor to arrest the cell cycle during G1 phase. The cells were released from G1 and collected every 10 minutes. Proteins were extracted from each sample and subjected to Western blot analysis to detect Cdc6-prA. Budding index is shown using the same samples. (C) Localization of Cdc6-GFP was analyzed in living cells. In wild type cells, nuclear accumulation of Cdc6-GFP was observed only in late mitotic cells (arrowhead) and not in small to medium budded cells (arrows), whereas Cdc6-GFP was observed in the nucleus throughout the cell cycle (arrowheads) in <i>mck1</i> deletion cells. (D) <i>CDC6-prA</i> or <i>Δmck1 CDC6-prA</i> cells were blocked at metaphase by nocodazole. The mitotic arrest was released upon removal of the drug. Cells were then incubated in YEPD and collected every 10 minutes. Proteins were extracted subjected to western blot analysis to detect CDC6-prA. Pgk1 was used as a loading control.</p>", "links"=>[], "tags"=>["cdc6p"], "article_id"=>200695, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g004", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mck1p_is_required_for_Cdc6p_degradation_/200695", "title"=>"Mck1p is required for Cdc6p degradation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:11:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/530013"], "description"=>"<p>(A) <i>ORC6-rxl mck1-16</i> cells were incubated either at 25 or 37°C and their protein extract was subjected to western blot analysis to detect Rad53-FLAG. (B) Strains with indicated genotypes were serially diluted 10 fold and plated on YEPD plates. The plates were incubated at the indicated temperature for 1–2 days. (C) Asynchronus populations of strains with indicated genotypes were grown at 25°C first. The temperature was shifted to 37°C for 8 hours and samples were collected. The cells were fixed, stained with propidium iodide and analyzed by FACS.</p>", "links"=>[], "tags"=>["was", "induced"], "article_id"=>200516, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g002", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_damage_was_induced_in_ORC6_rxl_mck1_16_cells_/200516", "title"=>"DNA damage was induced in <i>ORC6-rxl mck1-16</i> cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/529925"], "description"=>"<p>(A) <i>ORC-x::LEU2::HIS3/ORC6 mck1/MCK1-wt</i> diploid strains were sporulated, tetrads were dissected on YEPD plates, and the plates were incubated for 3 days at 30°C. <i>ORC6</i> alleles and <i>mck1</i> deletion were identified based on the markers. Inviable spores were genotyped by assuming a 2∶2 segregation. The <i>ORC6-rxl</i>, <i>ORC6-ps</i> or <i>ORC2-ps</i> alleles were indicated above each panel. The presence of <i>ORC6</i> mutant allele was marked as (m) and <i>ORC6</i> wild type as (+) on the left. The presence of <i>mck1</i> mutant allele (m) or <i>MCK1-wt</i> (+) was indicated on the right. (B) Strains with indicated genotypes were serially diluted 10 fold and plated on YEPD plates to test viability at different temperatures. The plates were incubated at the indicated temperature for 1–2 days. (C) Asynchronus populations of strains with indicated genotypes were grown at 26°C first. The temperature was shifted to 36°C and the samples were collected after 4 hours. The cells were fixed, stained with propidium iodide and analyzed by FACS. (D) Wild type, <i>mck1-16</i> or <i>ORC6-rxl mck1-16</i> cells were incubated at 36°C for 4 hours, and observed under the fluorescent microscope. Red color indicates nuclei stained by propidium iodide.</p>", "links"=>[], "tags"=>["lethality", "mitotic", "was", "induced"], "article_id"=>200413, "categories"=>["Biological Sciences"], "users"=>["Amy E. Ikui", "Valentina Rossio", "Lea Schroeder", "Satoshi Yoshida"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003099.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synthetic_lethality_and_mitotic_arrest_was_induced_in_the_ORC6_rxl_mck1_16_cells_/200413", "title"=>"Synthetic lethality and mitotic arrest was induced in the <i>ORC6-rxl mck1-16</i> cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-06 00:06:53"}

PMC Usage Stats | Further Information

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Relative Metric

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