Affinage

CDC6

Cell division control protein 6 homolog · UniProt Q99741

Length
560 aa
Mass
62.7 kDa
Annotated
2026-06-09
100 papers in source corpus 55 papers cited in narrative 55 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC6 is an essential AAA+ ATPase that licenses eukaryotic DNA replication origins by cooperating with ORC to load the MCM2-7 replicative helicase, and it has been conserved from archaea and yeast to humans as a master regulator coupling origin firing to cell cycle progression (PMID:2656692, PMID:7641697, PMID:16228006). Cdc6 binds ORC cooperatively on origin DNA in an ATP-dependent manner to form a ring-shaped, six-AAA+-subunit ORC-Cdc6 complex that bends origin DNA, rearranges ORC (including the Orc1 AAA+ domain and BAH/winged-helix elements), and creates the MCM2-7 recruitment sites absent from ORC alone (PMID:16228006, PMID:22405012, PMID:32848132, PMID:34162887). Cdc6's own winged-helix and initiator-specific motifs contact origin DNA within the ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) loading intermediate, through which DNA is threaded; the reaction proceeds via defined semi-attached and pre-insertion intermediates and an ORC-Cdc6-MCM (OCM) state competent for MCM2-7 dimerization (PMID:24234446, PMID:28191893, PMID:32669428). Cdc6 ATPase activity, activated by ORC and suppressed by origin DNA, is required not for loading itself but for Cdc6 disengagement from the pre-RC after helicase loading, a step essential for subsequent helicase activation (PMID:17314092, PMID:26305410). Cdc6 abundance, localization, and activity are tightly cell-cycle-controlled: human CDC6 transcription is driven by E2F factors and CDC6 cooperates with cyclin E to drive S-phase entry (PMID:9520412, PMID:9774682, PMID:11805305), while Cyclin A/CDK2 phosphorylation of N-terminal CDK sites drives nuclear-to-cytoplasmic relocalization and destruction of non-chromatin-bound Cdc6 to prevent re-replication (PMID:9889196, PMID:10806104). Cdc6 is degraded by sequential ubiquitin pathways—APC/C-CDH1 in G1 and quiescence, SCF-Cdc4, CRL4-Cdt2, SCF-Cyclin F late in the cycle, and the HECT ligase Huwe1 after DNA damage—and CDK/Clb binding to phosphorylated Cdc6 also inhibits pre-RC assembly (PMID:10995389, PMID:15496876, PMID:17567951, PMID:24434580, PMID:26818844). Beyond licensing, Cdc6 restrains mitotic entry by binding and inhibiting CDK complexes and acting cooperatively with Sic1 (PMID:1600944, PMID:11460169, PMID:12554670), represses the INK4/ARF and CDH1 loci through origin-coupled chromatin remodeling and HDAC recruitment with transforming activity (PMID:16572177, PMID:22201124), and obstructs apoptosome assembly by sequestering Apaf-1, while caspase-3 cleavage of Cdc6 during apoptosis generates nuclear pro-apoptotic, replication-inhibitory fragments (PMID:22493447, PMID:12151338, PMID:14517333). The deubiquitinase OTUD6A stabilizes CDC6 to promote tumor proliferation and chemoresistance (PMID:38685067).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1989 Medium

    Established CDC6 as an essential, conserved nucleotide-binding protein required for S-phase entry, defining the gene's core role before any mechanism was known.

    Evidence Complementation cloning, gene disruption, and sequencing in S. cerevisiae

    PMID:2656692

    Open questions at the time
    • No biochemical activity demonstrated
    • Molecular role at origins unknown
  2. 1990 Medium

    Showed CDC6 expression is cell-cycle periodic, peaking at G1/S, framing it as a transcriptionally gated licensing factor.

    Evidence Synchronized yeast cultures, Northern blotting, promoter analysis

    PMID:2246267

    Open questions at the time
    • Transcription factors driving periodicity not yet defined
    • Protein-level regulation unaddressed
  3. 1995 High

    Demonstrated that Cdc6 is required for replication initiation and that its absence uncouples replication from mitosis, revealing a checkpoint-like coupling function.

    Evidence Yeast genetics, synchronization, FISH, transcription factor mutants

    PMID:7641697

    Open questions at the time
    • Molecular mechanism of mitotic coupling unresolved
    • Direct origin role not yet shown
  4. 1996 High

    Identified Cdc6 as forming origin pre-replicative complexes distinct from ORC and as a binding partner/inhibitor of B-type cyclin/Cdc28 kinase, linking origin licensing to CDK control.

    Evidence Genomic footprinting at yeast origins; co-IP, pulldown, in vitro kinase assays, deletion mutants

    PMID:8930895 PMID:8978693

    Open questions at the time
    • Mechanism of CDK inhibition not structurally defined
    • How Cdc6 nucleates MCM loading unknown
  5. 1998 High

    Extended the model to humans: E2F-driven transcription, ORC1 and cyclin-CDK association, NLS-independent nuclear localization, and antibody-blocked replication established CDC6 as a conserved human licensing factor.

    Evidence Promoter-reporter, in vivo footprinting, antibody microinjection, fractionation, co-IP, NLS mutagenesis in human cells

    PMID:9520412 PMID:9566895 PMID:9774682

    Open questions at the time
    • Enzymatic requirement not yet tested in human protein
    • Mechanism of S-phase nuclear elimination unresolved
  6. 1999 High

    Defined Cdc6 ATPase activity as essential for replication and showed Cyclin A/CDK2 phosphorylation controls its localization, establishing both the catalytic requirement and the re-replication safeguard.

    Evidence Recombinant ATP binding/hydrolysis with Walker A/B mutants and microinjection; in vitro kinase, domain mapping, fractionation, immunofluorescence

    PMID:10436018 PMID:9857179 PMID:9889196

    Open questions at the time
    • Step in licensing requiring ATPase not yet pinpointed
    • How phosphorylation triggers export mechanistically unclear
  7. 2000 High

    Resolved that ubiquitin-mediated proteolysis (APC/C-CDH1 in G1/quiescence; SCF-Cdc4 in yeast) and Cyclin A-CDK2 phosphorylation selectively destroy non-chromatin-bound Cdc6, preventing re-licensing.

    Evidence In vitro APC/CDH1 ubiquitination, depletion, D-box/KEN-box mutagenesis; chromatin fractionation with recombinant Cyclin A-CDK2; yeast cdc4 epistasis

    PMID:10085159 PMID:10806104 PMID:10995389 PMID:9442103

    Open questions at the time
    • Coordination between distinct degradation pathways unresolved
    • Chromatin-bound vs soluble pool discrimination mechanism incomplete
  8. 2000 High

    Crystallography of an archaeal Cdc6 ortholog revealed the AAA+ fold with a DNA-binding winged-helix domain, providing the structural framework for origin recognition and showing both domains are functionally required.

    Evidence X-ray crystallography (2.0 A), WH and ATPase mutagenesis with S. pombe functional assays

    PMID:11030343

    Open questions at the time
    • Eukaryotic complex architecture not yet visualized
    • How WH domain engages origin DNA in ORC context unknown
  9. 2001 High

    Showed Cdc6 directly inactivates mitotic CDKs (with Sic1) and recruits Cyclin E-CDK2 to chromatin via RXL motifs, formalizing dual roles in licensing and mitotic restraint.

    Evidence Genetic CDK-domain deletion and epistasis, co-IP, in vitro CDK assays; Xenopus extract chromatin recruitment with RXL/MRAIL mutagenesis

    PMID:11257126 PMID:11460169

    Open questions at the time
    • Quantitative contribution of Cdc6 vs Sic1 to mitotic exit unclear
    • How chromatin-localized CDK2 acts on licensing not fully defined
  10. 2002 High

    Demonstrated Cdc6 alone suffices to load MCM and license origins in quiescent cells in an ATPase-dependent, cyclin E-CDK2-synergistic manner, and is required to re-establish replication competence in meiotic oocytes.

    Evidence Adenoviral wild-type/mutant Cdc6 with MCM chromatin assays; Xenopus oocyte Cdc6 protein injection with synthesis inhibition

    PMID:11805305 PMID:12384699

    Open questions at the time
    • Stoichiometry of MCM loading not defined
    • Mechanism of CDK isoform specificity unresolved
  11. 2003 Medium

    Provided first reconstituted Cdc6-MCM functional interaction (archaeal) and showed human Cdc6 overexpression in G2 blocks mitosis via a Chk1-dependent checkpoint, reinforcing replication-mitosis coupling.

    Evidence Archaeal recombinant biochemistry (EMSA, ATPase, MCM inhibition, Walker A mutant); G2 overexpression with UCN-01 and Cdc25 epistasis

    PMID:12554670 PMID:12966100

    Open questions at the time
    • Physiological relevance of G2 checkpoint role unclear
    • Direct human Cdc6-MCM contacts not yet structurally defined
  12. 2005 High

    Visualized the ring-shaped ORC-Cdc6 complex and showed Cdc6 tethering creates an artificial mammalian origin, establishing Cdc6 as the architectural trigger for origin assembly.

    Evidence ATP-dependent DNA binding, single-particle EM; GAL4-DBD tethering replication assay with ATPase mutants

    PMID:16228006 PMID:16322558

    Open questions at the time
    • Atomic detail of DNA engagement not yet resolved
    • MCM recruitment geometry unknown at this resolution
  13. 2006 High

    Revealed a non-licensing oncogenic function: high Cdc6 represses the INK4/ARF tumor suppressor locus via origin-coupled HDAC recruitment and heterochromatinization, with Ras-cooperative transforming activity.

    Evidence ChIP for Cdc6/Orc2/MCM at INK4/ARF, HDAC recruitment, RNAi heterochromatinization, transformation assays

    PMID:16572177

    Open questions at the time
    • Generality across other loci not yet established
    • Link between origin function and repression mechanistically incomplete
  14. 2007 High

    Defined the regulatory logic of Cdc6 ATPase—activated by ORC, suppressed by origin DNA—to stabilize productive ORC-Cdc6-DNA complexes at origins while dissociating Cdc6 from non-origin DNA.

    Evidence In vitro ATPase and complex-stability assays with multiple DNA substrates and mutants; co-IP, in vitro ubiquitination and Huwe1 knockdown for damage-induced turnover

    PMID:17314092 PMID:17567951

    Open questions at the time
    • Coupling of ATPase state to MCM loading step not yet resolved
    • Damage-induced chromatin release mechanism partly defined
  15. 2011 High

    Showed Cdc6 represses CDH1 (E-cadherin) by E-box binding, CTCF dissociation, and H2A.Z displacement, extending its chromatin-repressive and origin-activating activities to an EMT-relevant locus.

    Evidence ChIP for Cdc6/CTCF/H2A.Z, Walker B and C-terminal mutagenesis, origin activation assay

    PMID:22201124

    Open questions at the time
    • In vivo tumor relevance not directly tested here
    • How replication and repression activities are coordinated unclear
  16. 2012 Medium

    Provided cryo-EM of ORC-Cdc6 on origin DNA and revealed Cdc6's anti-apoptotic function via Apaf-1 sequestration, broadening its role to cell survival.

    Evidence Single-particle cryo-EM with footprinting; co-IP with Apaf-1, apoptosome assembly assay with domain mutants

    PMID:22405012 PMID:22493447

    Open questions at the time
    • Apaf-1 interaction structurally undefined
    • Physiological threshold of anti-apoptotic activity unknown
  17. 2013 High

    Identified the ORC-Cdc6-MCM (OCM) intermediate as the Cdc6-dependent, dimerization-competent step distinguishing it from the earlier OCCM, defining the rate-limiting transition in helicase loading.

    Evidence Biochemical pre-RC reconstitution, MCM interface mutants, EM, salt-sensitivity assays

    PMID:24234446

    Open questions at the time
    • Conformational basis of dimerization competence not yet atomic
    • Timing relative to Cdt1 release unclear
  18. 2015 High

    Demonstrated definitively that Cdc6 ATPase is required for post-loading disengagement of Cdc6, not MCM loading itself—resolving a long-standing question about the catalytic step.

    Evidence Reconstituted loading with Cdc6-E224Q ATPase mutant plus in vivo conditional degradation rescue

    PMID:26305410

    Open questions at the time
    • How disengagement enables helicase activation mechanistically unclear
    • Structural state of disengaged complex undefined
  19. 2016 High

    Added SCF-Cyclin F as a late-cycle CDC6 degradation pathway guarding against re-replication, and showed ORC1/CDC6 form an opposing transcriptional circuit at CCNE1, integrating licensing with cell-cycle commitment.

    Evidence Co-IP, ubiquitination, re-replication flow cytometry with stable mutant; ORC1-RB-SUV39H1 co-IP/ChIP with CDC6 RB-displacement assay

    PMID:26818844 PMID:27458800

    Open questions at the time
    • Redundancy among degradation pathways not quantified
    • Direct demonstration of feedback circuit in normal proliferation incomplete
  20. 2017 High

    Near-atomic cryo-EM of the OCCM and discovery of Cdc6 at centrioles revealed both the structural basis of origin licensing and a moonlighting role limiting centrosome duplication.

    Evidence Cryo-EM of OCCM at 3.9 A with crosslinking MS; co-IP with Sas-6/STIL, centrosome assays, Plk4 phosphorylation

    PMID:28191893 PMID:28447620

    Open questions at the time
    • DNA insertion step not captured
    • Physiological extent of centrosome regulation unclear
  21. 2020 High

    Captured loading intermediates and DNA bending mechanics by cryo-EM and MD, showing how Cdc6 binding promotes DNA bending and stepwise MCM2-7 engagement toward the loaded state.

    Evidence Cryo-EM of Drosophila ORC +/- Cdc6 and yeast semi-attached/pre-insertion OCCM with molecular dynamics

    PMID:32669428 PMID:32848132

    Open questions at the time
    • Full DNA insertion and gate closure dynamics still inferred
    • How ATPase activity drives these transitions not resolved
  22. 2021 High

    Resolved at 3.3 A how Cdc6 contributes to origin recognition and allosterically activates its own ATPase by rearranging ORC, and defined CDC6 disordered-region SLiMs governing cyclin-CDK and ORC1 interactions.

    Evidence Cryo-EM at 3.3 A; SLiM mutagenesis with co-IP and CDK2 assays

    PMID:33761311 PMID:34162887

    Open questions at the time
    • Dynamics of ATPase activation during loading still modeled, not observed
    • Functional hierarchy of individual SLiMs incomplete
  23. 2024 High

    Identified OTUD6A as a deubiquitinase that stabilizes CDC6 to drive tumor proliferation and chemoresistance, providing a disease-relevant post-translational control point.

    Evidence DUB screen, co-IP, in vitro deubiquitination, half-life assays, conditional KO mouse, xenograft bladder cancer model

    PMID:38685067

    Open questions at the time
    • Whether OTUD6A acts on chromatin-bound vs soluble CDC6 unknown
    • Generality across cancer types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Cdc6 ATPase-driven disengagement is mechanically coupled to helicase activation, and how its licensing function is integrated with its chromatin-repressive, anti-apoptotic, and centrosomal roles in a single cell, remain unresolved.
  • No structure of the disengaged post-loading state
  • Mechanism connecting origin function to transcriptional repression unclear
  • How moonlighting functions are temporally partitioned from licensing unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 4 GO:0016787 hydrolase activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-69306 DNA Replication 6 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-4839726 Chromatin organization 2
Partners
APAF1CCNA2CCNE1CDT1HUWE1MCM2-7ORC1OTUD6A
Complex memberships
ORC-Cdc6ORC-Cdc6-Cdt1-Mcm2-7 (OCCM)ORC-Cdc6-Mcm2-7 (OCM)pre-replicative complex

Evidence

Reading pass · 55 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CDC6 gene encodes an essential protein for S phase entry in S. cerevisiae; the deduced protein sequence contains a conserved nucleotide-binding site, and disruption of CDC6 is lethal for mitotic growth. Complementation cloning, gene disruption, DNA sequencing The Journal of biological chemistry Medium 2656692
1990 CDC6 mRNA is periodically expressed in the yeast cell cycle, peaking at the G1/S boundary, and the CDC6 promoter contains sequence elements (similar to those in other cell cycle-regulated genes) that drive this periodic transcription. Synchronized culture experiments (alpha-factor arrest, elutriation), Northern blotting, promoter sequence analysis The Journal of biological chemistry Medium 2246267
1992 Constitutive CDC6 expression in yeast delays initiation of M phase in a manner dependent on the Wee1/Mik1 mitotic inhibitor kinases and is counteracted by Cdc25/MIH1 phosphatases, indicating CDC6 indirectly inhibits activation of p34cdc2/CDC28 M-phase kinase; CDC6 thus has a dual role in requiring DNA replication initiation and suppressing nuclear division. Constitutive expression of CDC6 in budding and fission yeast, genetic interaction analysis with wee1, mik1, cdc25, MIH1 mutants The EMBO journal Medium 1600944
1994 Purified S. cerevisiae Cdc6 protein binds rATP and rGTP upon UV cross-linking and catalyzes DNA-independent hydrolysis of purine nucleoside triphosphates, consistent with an ATPase/GTPase activity that may regulate replication initiation. Recombinant protein expression in E. coli, UV cross-linking nucleotide binding assay, ATPase/GTPase activity assay The Journal of biological chemistry Medium 8083240
1995 Cdc6 is an unstable protein whose de novo synthesis in G1 (driven first by Swi5, then by MBF/SBF transcription factors) is required for initiation of DNA replication; cells lacking Cdc6 fail to replicate DNA but still undergo mitosis ('reductional anaphase'), demonstrating that Cdc6 deficiency uncouples DNA replication from mitotic entry. Yeast genetics, cell synchronization, fluorescence in situ hybridization (FISH), transcription factor mutant analysis The EMBO journal High 7641697
1996 ORC and Cdc6 form distinct chromatin complexes at replication origins in S. cerevisiae: origins oscillate between an ORC-dependent post-replicative state and a Cdc6-dependent pre-replicative state during the cell cycle. Genomic footprinting at single-copy chromosomal origins in yeast The EMBO journal High 8978693
1996 Yeast Cdc6 physically interacts with B-type cyclin/Cdc28 kinase complexes (not Cln/Cdc28); Cdc6 is a substrate and inhibitor of Cdc28 kinase in vitro; the Cdc28-interaction domain of Cdc6 is required for its essential growth function and for restraining mitosis. Co-immunoprecipitation, p13-agarose pulldown, affinity chromatography with bacterially produced Cdc6, in vitro kinase assay, deletion mutant analysis Molecular biology of the cell High 8930895
1998 Human CDC6 transcription is regulated by E2F transcription factors; E2F binding sites in the CDC6 promoter are required for cell cycle-regulated expression; microinjection of anti-CDC6 antibody blocks initiation of DNA replication in human tumor cells. Promoter-reporter assay, in vivo footprinting, microinjection of antibody, E2F overexpression Proceedings of the National Academy of Sciences of the United States of America High 9520412
1998 Human CDC6/Cdc18 is nuclear in G1 and is selectively eliminated from the nucleus at the onset of S phase; it associates with human Orc1 protein and cyclin-CDK complexes; nuclear localization is independent of its nuclear localization signal, implying association with other nuclear proteins. Epitope-tagged protein cell cycle fractionation, co-immunoprecipitation with Orc1 and cyclin-CDKs, site-directed mutagenesis of NLS Molecular and cellular biology High 9566895
1998 Mammalian CDC6 promoter is activated by E2F proteins; E2F binding sites are required for serum-stimulated and cell cycle-regulated expression; CDC6 cooperates with cyclin E to induce S phase entry; microinjection of anti-CDC6 antiserum blocks DNA synthesis. Promoter-reporter assay, E2F overexpression, co-transfection with cyclin E, antibody microinjection Molecular and cellular biology High 9774682
1998 Recombinant human Cdc6 (HsCdc6) specifically binds ATP and slowly hydrolyzes it; Walker A and B motif mutants are defective in ATP binding/hydrolysis and display aberrant conformations in the presence of nucleotides; microinjection of either mutant inhibits DNA replication in G1 cells, demonstrating that Cdc6 ATPase activity is essential for DNA replication. Recombinant protein expression, ATP binding and hydrolysis assays, mutagenesis of Walker A and B motifs, microinjection into human cells Molecular biology of the cell High 10436018
1998 Cdc6 protein causes premature entry into S phase: addition of recombinant Cdc6 to permeabilized G1 nuclei induces up to 82% of nuclei to initiate DNA replication and accelerates G1 progression in a mammalian cell-free system; quiescent cells lack Cdc6 and fail to load MCM proteins onto chromatin. Mammalian cell-free DNA replication system, recombinant Cdc6 addition, immunoblot for Cdc6 and MCM chromatin association The EMBO journal High 9857179
1999 Mammalian CDC6 is phosphorylated specifically by Cyclin A/CDK2 (not Cyclin E or Cyclin B) via an N-terminal Cy-motif; phosphorylation of three N-terminal CDK consensus sites regulates CDC6 subcellular localization; CDC6 is nuclear in G1 and relocalizes to the cytoplasm upon Cyclin A/CDK2 activation, suggesting phosphorylation prevents re-replication. In vitro kinase assay, co-immunoprecipitation, cyclin binding domain mapping, ectopic Cyclin A/E expression, subcellular fractionation and immunofluorescence The EMBO journal High 9889196
1999 S. cerevisiae Cdc6 protein is ubiquitinated in vivo and degraded by a Cdc4-dependent (SCF) ubiquitin-mediated proteolytic pathway at the late G1/early S phase transition. In vivo ubiquitination assay, analysis of Cdc6 stability in cdc4 mutants, cell cycle synchronization The Journal of biological chemistry Medium 10085159
1999 After formation of pre-initiation complexes (ORC, Cdc6, MCM on chromatin), Cdc6 is rapidly removed from chromatin in Xenopus extracts, possibly via a cdk2-activated ubiquitin-dependent proteolytic pathway; inhibition of this removal blocks DNA replication initiation; subsequent initiation steps are independent of ORC and Cdc6 but dependent on cdk2 activity. Xenopus laevis egg extract system, chromatin fractionation, cdk2 inhibition, ubiquitin pathway interference The Journal of cell biology High 9442103
2000 Human CDC6 is targeted for ubiquitin-mediated proteolysis by APC/C-CDH1 in G1 and quiescent cells; point mutations in both the destruction box and KEN-box motifs together stabilize CDC6; APC/CDH1 ubiquitinates CDC6 in vitro; APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. In vitro ubiquitination assay with purified APC/CDH1, APC/CDH1 depletion, mutagenesis of destruction box and KEN box, stability assays in G1 and quiescent cells Genes & development High 10995389
2000 Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a process requiring nuclear import and phosphorylation by a chromatin-bound kinase; recombinant Cyclin A-CDK2 completely substitutes for the nucleus in promoting destruction of soluble Cdc6, suggesting that Cyclin A-CDK2 phosphorylation destroys free Cdc6 not assembled into replication complexes. Mammalian cell extract in vitro replication system, chromatin fractionation, recombinant Cyclin A-CDK2 addition, nuclear import inhibition Journal of cell science High 10806104
2000 Cdc6 stability in S. cerevisiae is regulated by Cdc28 (CDK1)/Clb kinase activity; Cdc6 mutants lacking Cdc28 phosphorylation sites are stabilized; loss of Cdc28/Clb kinase activity allows accumulation of Cdc6 protein in mitotic-arrested cells. Cell cycle synchronization, protein stability assays, phosphorylation-site mutant analysis, temperature-sensitive cdc28 mutants The Journal of biological chemistry Medium 10734126
2000 Crystal structure of an archaeal Cdc6 ortholog (2.0 Å) reveals an AAA+-type nucleotide binding fold bound to Mg·ADP and a winged-helix (WH) domain similar to known DNA-binding modules; mutagenesis of the WH domain of S. pombe Cdc18 shows this region is required for function in vivo; nucleotide binding/hydrolysis by Cdc6/Cdc18 is required for S phase progression and for maintenance of S-phase checkpoint control. X-ray crystallography (2.0 Å), site-directed mutagenesis of WH domain and ATPase motifs, in vivo functional assays in S. pombe Molecular cell High 11030343
2001 Cyclin E binds the N-terminal region of Cdc6 via RXL (Cy) motifs on Cdc6 and the substrate-selection (MRAIL) motif on Cyclin E; this interaction localizes Cyclin E-CDK2 to chromatin in an ORC- and Cdc6-dependent manner; mutation of the RXL motifs in Cdc6 abrogates Cyclin E binding and rescuing of replication in Cdc6-depleted Xenopus extracts. Xenopus egg extract chromatin assembly assay, domain mapping, site-directed mutagenesis of RXL and MRAIL motifs, rescue assays with Cdc6-depleted extracts The Journal of cell biology High 11257126
2001 Cdc6 expression in fission yeast G2 cells overrides controls that ensure one S phase per cycle by re-firing replication origins and recruiting MCM Cdc21 to chromatin; co-expression of Cdt1 greatly amplifies this re-replication; Cdt1 may stabilize Cdc18 on chromatin. Inducible expression in S. pombe G2 cells, FACS analysis, MCM chromatin association, phosphorylation-site mutant analysis The EMBO journal Medium 11532929
2001 Cdc6 cooperates with Sic1 to inactivate mitotic CDKs during late mitosis in S. cerevisiae; deletion of the CDK-interacting domain of Cdc6 causes a mitotic exit delay that is accentuated in the absence of Sic1 or cyclin degradation; Cdc6, like Sic1, binds CDK complexes in vivo and downregulates them in vitro. Genetic deletion of Cdc6 CDK-binding domain, double mutant analysis with sic1 and cyclin degradation mutants, co-immunoprecipitation, in vitro CDK kinase assay Nature High 11460169
2002 Human Cdc6 is rapidly destroyed by a proteasome- and ubiquitin-dependent pathway during early apoptosis induced by adozelesin (p53-independent) and by a separate caspase-dependent pathway during TNF-α-induced apoptosis; the proteasome-dependent pathway is conserved in S. cerevisiae. Western blot of Cdc6 during apoptosis, proteasome inhibitor, p53-null cell lines, cross-species comparison Molecular biology of the cell Medium 12006651
2002 Mammalian Cdc6 expression alone (via adenoviral vector) is sufficient to induce stable MCM chromatin association in quiescent cells with low CDK activity; Cdc6 ATP-binding site mutation severely impairs MCM loading; Cdc6 synergizes with cyclin E/CDK2 (but not cyclin A/CDK2) to induce semiconservative DNA replication in quiescent cells. Adenoviral expression of wild-type and mutant Cdc6 in quiescent cells, chromatin fractionation for MCM, semiconservative replication assay, CDK co-expression Proceedings of the National Academy of Sciences of the United States of America High 11805305
2002 Xenopus Cdc6 synthesis during meiosis I (at germinal vesicle breakdown, GVBD) is necessary and sufficient for re-establishing DNA replication competence in oocytes; injection of Cdc6 protein into GVBD oocytes induces DNA replication in the absence of other protein synthesis. Xenopus oocyte injection of recombinant Cdc6 protein, replication competence assay, protein synthesis inhibition Nature High 12384699
2002 Human Cdc6 is specifically cleaved by caspase-3 during apoptosis; expression of a caspase-uncleavable Cdc6 mutant attenuates apoptosis, demonstrating that Cdc6 cleavage facilitates cell death and prevents a wounded cell from replicating. Western blot of Cdc6 cleavage during apoptosis in multiple cell lines, expression of cleavage-resistant Cdc6 mutant, apoptosis assays EMBO reports Medium 12151338
2003 Caspase-3 cleaves Cdc6 at SEVD442/G site during apoptosis, generating p49-tCdc6 that lacks the C-terminal nuclear export sequence; p49-tCdc6 is retained in the nucleus (resistant to Cyclin A-CDK2-mediated export), acts as a dominant negative inhibitor of DNA replication, and promotes apoptosis when ectopically expressed. In vitro caspase-3 cleavage assay, mutagenesis of cleavage sites, subcellular fractionation, ectopic expression of truncated Cdc6, apoptosis assays Molecular biology of the cell Medium 14517333
2003 Human Cdc6 overexpression in G2 phase prevents entry into mitosis via a Chk1-dependent checkpoint; this block is abolished by constitutively active Cyclin B/CDK1, Cdc25B, or Cdc25C, or by the Chk1 inhibitor UCN-01; overexpressed Cdc6 in G2 induces Chk1 phosphorylation. Ectopic HuCdc6 overexpression in G2-phase cells, kinase inhibitor (UCN-01), Cdc25 co-expression, flow cytometry, Chk1 phosphorylation assay The EMBO journal Medium 12554670
2003 Biochemical characterization of archaeal Cdc6 (SsoCdc6-1 from Sulfolobus solfataricus): binds ssDNA and dsDNA, has weak ATPase activity, undergoes autophosphorylation; Walker A mutant (K59A) abolishes ATPase and autophosphorylation; SsoCdc6-1 strongly inhibits ATPase and DNA helicase activity of S. solfataricus MCM—the first in vitro evidence of functional Cdc6-MCM interaction. Recombinant protein expression, EMSA, ATPase assay, autophosphorylation assay, Walker A mutagenesis, MCM helicase inhibition assay The Journal of biological chemistry High 12966100
2004 Mitotic CDK Clb2/Cdc28 binds tightly to an N-terminal domain (NTD) of Cdc6 only when the NTD is phosphorylated on CDK consensus sites; Cdc6 in this complex cannot assemble pre-RCs; human CDKs with cyclins A, B, and E also bind phospho-NTD peptides; this Clb2-dependent mechanism contributes to preventing re-replication in vivo. In vitro binding assays with recombinant Clb2 and synthetic phospho-NTD peptides, co-IP, pre-RC assembly assay, in vivo re-replication assay Nature High 15496876
2004 CDC6 is required for meiotic spindle formation in mouse oocytes; RNAi-mediated knockdown of CDC6 prevents meiotic spindle assembly without affecting resumption of meiosis, revealing a role for CDC6 in spindle organization beyond its established function in DNA replication. RNA interference knockdown of CDC6 in mouse oocytes, meiotic spindle immunofluorescence Biology of reproduction Medium 15385409
2005 S. cerevisiae Cdc6 binds cooperatively with ORC on origin DNA in an ATP-dependent manner, inducing a change in origin binding pattern that requires the Orc1 ATPase; single-particle EM reconstruction shows ORC-Cdc6 forms a ring-shaped complex with dimensions similar to the MCM helicase, predicted to contain six AAA+ subunits. ATP-dependent DNA binding assays, origin mutation analysis, single-particle electron microscopy reconstruction Nature structural & molecular biology High 16228006
2005 Recruitment of CDC6 (as a GAL4-DBD fusion) to a defined DNA array is sufficient to create a functional artificial origin of replication in mammalian cells; the ATPase domain of human Cdc6 is functionally important; N-terminal segments of ORC1/ORC2 are dispensable in this assay. GAL4-DBD fusion tethering assay, replication assay with geminin inhibition, ATPase domain mutant analysis Genes & development Medium 16322558
2005 p53 activation by DNA damage enhances Cdc6 destruction via the APC; this destruction is triggered by inhibition of CDK2-mediated phosphorylation of CDC6 at serine 54; suppression of p53 stabilizes Cdc6, leading to more replicating cells—an effect reversed by reducing Cdc6 levels. DNA damage treatment, CDK2 inhibition, p53 knockdown, Cdc6 stability assays, phosphorylation-site mutagenesis Molecular and cellular biology Medium 16055707
2006 High levels of Cdc6 repress transcription of the INK4/ARF locus (p15INK4b, ARF, p16INK4a) through a replication origin (RD-INK4/ARF) that assembles Cdc6/Orc2/MCM complexes; Cdc6 overexpression recruits histone deacetylases and induces heterochromatinization of this locus; Cdc6 has cellular immortalization and transformation activities in cooperation with Ras. ChIP for Cdc6/Orc2/MCM at INK4/ARF locus, RNAi-induced heterochromatinization, HDAC recruitment assay, transformation assays Nature High 16572177
2006 Cdc6 depletion during S phase (not G1) slows DNA replication and leads to mitotic lethality; Cdc6-depleted S-phase cells show fewer newly fired origins but active established replication forks; loss of Cdc6 in S phase fails to activate Chk1 kinase. RNAi-mediated depletion in synchronous G1 vs S-phase cells, origin firing analysis, Chk1 activation assay, mitotic outcome analysis EMBO reports Medium 16439999
2006 Caspase-3 cleaves Cdc6 at D290/S and D442/G sites during apoptosis; resulting truncated fragments (p32-tCdc6 and p49-tCdc6) promote apoptosis, perturb MCM2 (but not Orc2) chromatin loading, and activate ATM and ATR kinases with kinetics consistent with Chk1/2 phosphorylation. In vitro caspase-3 cleavage mapping, ectopic expression of tCdc6 fragments, chromatin loading assay for MCM2/Orc2, ATM/ATR kinase activation assay, siRNA for ATM/ATR The Journal of cell biology Medium 16801388
2007 Cdc6 ATPase activity is activated by ORC, regulates ORC-Cdc6 complex stability, and is suppressed by origin DNA; specific origin DNA sequences (particularly the A element) down-regulate Cdc6 ATPase, resulting in stable ORC-Cdc6-DNA complex formation competent for MCM loading; on non-origin DNA, Cdc6 ATPase promotes Cdc6 dissociation. In vitro ATPase assay with ORC and various DNA sequences, ATPase mutants, ORC-Cdc6 complex stability assays on different DNAs The Journal of biological chemistry High 17314092
2007 Cdc6 stability after UV irradiation or MMS-induced DNA damage is regulated by the HECT-family ubiquitin E3 ligase Huwe1 (Mule/ARF-BP1); Cdc6 directly binds Huwe1; Huwe1 polyubiquitinates Cdc6 in vitro; this pathway is independent of p53, Cdc6 CDK-phosphorylation sites, and APC-Cdh1; it is conserved in yeast (Tom1 ortholog) and is associated with Cdc6 release from chromatin. Co-IP of Cdc6 with Huwe1, in vitro ubiquitination assay, Huwe1 knockdown, Tom1 deletion in yeast, UV/MMS treatment Molecular biology of the cell High 17567951
2011 Cdc6 represses CDH1 (E-cadherin) transcription by binding to E-boxes in the CDH1 promoter, causing dissociation of the insulator CTCF, displacement of histone variant H2A.Z, and promoter heterochromatinization; mutational analysis identifies the Walker B motif and C-terminal region of Cdc6 as essential for this transcriptional suppression; CTCF displacement also activates adjacent replication origins. ChIP for Cdc6, CTCF, H2A.Z at CDH1 promoter, overexpression of Cdc6 in epithelial cells, mutational analysis of Walker B and C-terminal domain, replication origin activation assay The Journal of cell biology High 22201124
2012 Cryo-EM structure of S. cerevisiae ORC-Cdc6 on ARS1 origin DNA shows Cdc6 binding changes ORC conformation, particularly reorienting the Orc1 N-terminal BAH domain; a single Cdc6 extends the ORC footprint on origin DNA from both ends; the crescent-like ORC bends and wraps DNA. Single-particle cryo-EM, docking of archaeal Orc1/Cdc6 crystal structure, DNase I footprinting Structure High 22405012
2012 Cdc6 obstructs apoptosome assembly by forming stable complexes with cytochrome c-activated Apaf-1 monomers; this function depends on Cdc6's ATPase domain but not its cyclin-binding motif; in proliferating cells, Cdc6 suppresses seemingly unintended apoptosis while promoting cell proliferation. Co-immunoprecipitation of Cdc6 with Apaf-1, apoptosome assembly assay, ATPase domain mutant and cyclin-binding motif mutant analysis The Journal of biological chemistry Medium 22493447
2012 A yeast GSK-3 kinase homolog Mck1 promotes Cdc6 degradation by phosphorylating Cdc6 at Threonine-368 (a GSK-3 consensus site), leading to SCF(CDC4)-dependent proteolysis; mck1 deletion stabilizes Cdc6 in late S phase and mitosis; Mck1-dependent Cdc6 degradation is required to prevent DNA re-replication. Deletion analysis of MCK1, protein stability assays, phosphorylation-site mutagenesis (T368A), SCF genetic epistasis, DNA content analysis for re-replication PLoS genetics Medium 23236290
2013 During pre-RC assembly, ORC-Cdc6 forms an intermediate ORC-Cdc6-MCM2-7 (OCM) complex that is competent for MCM2-7 dimerization; the initial ORC-Cdc6-Cdt1-MCM2-7 (OCCM) complex is not competent for dimerization; MCM2-7 dimerization is a limiting, Cdc6-dependent step in pre-RC formation. Biochemical reconstitution of pre-RC assembly, MCM2-7 hexamer-interface mutants, complex analysis by EM, salt-sensitivity assays Nucleic acids research High 24234446
2014 A PIP-box in the N-terminus of Cdc6 mediates APC/C-CDH1-independent degradation of nuclear Cdc6 at the G1-S transition and during S phase via the CRL4-Cdt2 complex, preventing nuclear Cdc6 re-accumulation; Cdk1 contributes to nuclear export of Cdc6 at the S-to-G2 transition. PIP-box mutagenesis, Cdt2 knockdown, cell cycle synchronization, nuclear/cytoplasmic fractionation, Cdc6 stability assays Journal of cell science Medium 24434580
2015 Cdc6 ATPase activity is required for Cdc6 disengagement from the pre-RC after MCM helicase loading, not for MCM loading per se; an ATPase-defective Cdc6-E224Q mutant supports MCM loading but cells remain blocked in G1; degradation of Cdc6-E224Q after MCM loading restores apparently normal S phase, demonstrating that Cdc6 must disengage post-loading to allow helicase activation. Purified protein reconstitution of MCM loading with Cdc6 ATPase mutants, in vivo MCM chromatin association, conditional Cdc6 degradation experiments, S phase progression assay eLife High 26305410
2016 SCF(Cyclin F) ubiquitin ligase complex targets CDC6 for proteasomal degradation late in the cell cycle through defined sequence motifs; absence of Cyclin F or expression of a stable CDC6 mutant promotes DNA re-replication and genome instability in cells lacking Geminin. Co-IP of CDC6 with Cyclin F, ubiquitination assay, stable CDC6 mutant expression, re-replication assay by flow cytometry, Geminin depletion Nature communications High 26818844
2016 ORC1 represses Cyclin E gene (CCNE1) transcription by binding RB, the histone methyltransferase SUV39H1, and its repressive H3K9me3 mark; in contrast, CDC6 binds Cyclin E-CDK2 and removes RB from ORC1 in a feedback loop, thereby hyper-activating CCNE1 transcription; ORC1 and CDC6 thus have opposing effects on cell cycle commitment. Co-IP of ORC1 with RB and SUV39H1, ChIP for H3K9me3, promoter reporter assay, CDC6 overexpression removing RB from ORC1 eLife Medium 27458800
2017 Cryo-EM structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) at 3.9 Å shows Cdc6 winged-helix domain and positively charged loops contact origin DNA; flexible Mcm2-7 winged-helix domains engage ORC-Cdc6; DNA passes through both the ORC-Cdc6 and Mcm2-7 rings; Cdt1 embraces Mcm2, Mcm4, and Mcm6 comprising nearly half the hexamer. Cryo-EM structure determination at 3.9 Å resolution, crosslinking mass spectrometry Nature structural & molecular biology High 28191893
2017 Cdc6 is recruited to centrioles via Cyclin A and negatively regulates centrosome duplication by binding Sas-6, inhibiting stable Sas-6/STIL complex formation; Plk4 phosphorylates Cdc6 to disrupt Cdc6-Sas-6 interaction, counteracting Cdc6's inhibitory role on centrosome duplication; Cdc6 and Plk4 thus antagonistically control centrosome number. Co-IP of Cdc6 with Sas-6 and STIL, immunofluorescence for Cdc6 at centrosomes, Plk4 phosphorylation of Cdc6, centrosome duplication assay with Cdc6 mutants Nature communications Medium 28447620
2020 Cryo-EM structures of Drosophila ORC with and without Cdc6 reveal that Orc1 and Orc4 constitute the primary DNA binding site; a Walker B loop of Orc1 contacts DNA, allosterically coupling DNA binding to the ATPase site; Cdc6 binding promotes DNA bending which facilitates MCM2-7 loading in vitro. Cryo-EM structure of Drosophila ORC ± Cdc6 on DNA, biochemical DNA-binding and MCM loading assays Nature communications High 32848132
2020 Two ORC-Cdc6-Cdt1-Mcm2-7 loading intermediates prior to DNA insertion were captured by cryo-EM: 'semi-attached OCCM' where Mcm3 and Mcm7 WHDs latch onto ORC-Cdc6 without the main body docking, and 'pre-insertion OCCM' where Mcm2-7 docks and origin DNA is bent adjacent to the Mcm2-Mcm5 open gate; molecular simulations show dynamic transition to the fully loaded state. Cryo-EM of loading intermediates (Mcm6-WHD truncation to slow reaction), molecular dynamics simulations Proceedings of the National Academy of Sciences of the United States of America High 32669428
2021 Cryo-EM structure of S. cerevisiae ORC-Cdc6 on ARS1 origin DNA at 3.3 Å reveals that Cdc6 contributes to origin DNA recognition via its winged-helix domain and initiator-specific motif; Cdc6 binding rearranges an α-helix in the Orc1 AAA+ domain and the Orc2 WHD, activating the Cdc6 ATPase and forming three Mcm2-7 recruitment sites absent in ORC alone. Cryo-EM at 3.3 Å resolution Nature communications High 34162887
2021 Multiple short linear motifs (SLiMs) in the intrinsically disordered region (IDR) of CDC6 mediate cyclin-CDK-dependent and -independent interactions; the CDC6 Cy motif cooperates with cyclin E-CDK2 to promote ORC1-CDC6 interaction in G1; the CDC6 IDR regulates ORC1 self-interaction and controls ORC1 protein levels; Protein Phosphatase 1 binds ORC1 IDR causing de-phosphorylation at mitotic exit. Co-IP of CDC6 SLiM mutants with cyclins and ORC1, CDK2 kinase assays, cell cycle synchronization with protein level measurements Molecular cell Medium 33761311
2024 The deubiquitinase OTUD6A interacts with, deubiquitinates (removing K6-, K33-, and K48-linked polyubiquitin chains), and stabilizes CDC6 protein; OTUD6A promotes tumor cell proliferation and chemoresistance via CDC6 upregulation; OTUD6A-CDC6 axis is conserved in an in vivo bladder cancer model. Proteome-wide DUB screening, co-IP of OTUD6A with CDC6, in vitro deubiquitination assay, protein half-life assay, conditional Otud6a KO mouse model, xenograft model Molecular cancer High 38685067

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Cdc6 is an unstable protein whose de novo synthesis in G1 is important for the onset of S phase and for preventing a 'reductional' anaphase in the budding yeast Saccharomyces cerevisiae. The EMBO journal 348 7641697
1999 Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. The EMBO journal 347 9889196
2018 LncRNA-CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215. Journal of cellular physiology 255 30362551
2000 Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Genes & development 231 10995389
1998 Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 228 9520412
1998 Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Molecular and cellular biology 220 9566895
2007 CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Carcinogenesis 207 18048387
2000 Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control. Molecular cell 188 11030343
2005 p16INK4A, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer. Journal of clinical pathology 187 15858126
1998 Identification of a preinitiation step in DNA replication that is independent of origin recognition complex and cdc6, but dependent on cdk2. The Journal of cell biology 183 9442103
2005 ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA. Nature structural & molecular biology 176 16228006
1998 Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F. Molecular and cellular biology 159 9774682
2006 Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Nature 145 16572177
2017 Structural basis of Mcm2-7 replicative helicase loading by ORC-Cdc6 and Cdt1. Nature structural & molecular biology 141 28191893
1996 ORC- and Cdc6-dependent complexes at active and inactive chromosomal replication origins in Saccharomyces cerevisiae. The EMBO journal 141 8978693
1998 Cdc6 protein causes premature entry into S phase in a mammalian cell-free system. The EMBO journal 133 9857179
1992 Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division. The EMBO journal 128 1600944
2007 Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Molecular biology of the cell 121 17567951
2001 Cyclin E uses Cdc6 as a chromatin-associated receptor required for DNA replication. The Journal of cell biology 107 11257126
2002 Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. Proceedings of the National Academy of Sciences of the United States of America 100 11805305
1996 Interaction between yeast Cdc6 protein and B-type cyclin/Cdc28 kinases. Molecular biology of the cell 99 8930895
1998 Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F. Oncogene 97 9778043
2000 Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a cyclin A-cdk2 dependent process. Journal of cell science 95 10806104
2004 Phosphorylation-dependent binding of mitotic cyclins to Cdc6 contributes to DNA replication control. Nature 86 15496876
2016 SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication. Nature communications 84 26818844
2003 Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1. The EMBO journal 80 12554670
2011 Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins. The Journal of cell biology 79 22201124
2007 Cdc6 ATPase activity regulates ORC x Cdc6 stability and the selection of specific DNA sequences as origins of DNA replication. The Journal of biological chemistry 79 17314092
2001 Expression of Cdc18/Cdc6 and Cdt1 during G2 phase induces initiation of DNA replication. The EMBO journal 77 11532929
1994 The Saccharomyces cerevisiae CDC6 gene is transcribed at late mitosis and encodes a ATP/GTPase controlling S phase initiation. The Journal of biological chemistry 77 8083240
1999 Cyclin A-dependent kinase activity affects chromatin binding of ORC, Cdc6, and MCM in egg extracts of Xenopus laevis. European journal of biochemistry 73 10491086
2012 Estrogen-induced upregulation and 3'-UTR shortening of CDC6. Nucleic acids research 71 22977174
2006 The functional role of Cdc6 in S-G2/M in mammalian cells. EMBO reports 71 16439999
2017 Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling. Cell reports 69 28228262
2002 Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast. Molecular biology of the cell 67 12006651
2001 Cdc6 cooperates with Sic1 and Hct1 to inactivate mitotic cyclin-dependent kinases. Nature 67 11460169
2005 p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation. Molecular and cellular biology 66 16055707
1999 The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells. Molecular biology of the cell 66 10436018
2019 Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes. Cell death & disease 64 30894513
2016 Juvenile Hormone Activates the Transcription of Cell-division-cycle 6 (Cdc6) for Polyploidy-dependent Insect Vitellogenesis and Oogenesis. The Journal of biological chemistry 62 26728459
2005 Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells. Genes & development 62 16322558
2010 DnaA, ORC, and Cdc6: similarity beyond the domains of life and diversity. Biochemistry and cell biology = Biochimie et biologie cellulaire 58 20130679
2012 Cdc6-induced conformational changes in ORC bound to origin DNA revealed by cryo-electron microscopy. Structure (London, England : 1993) 56 22405012
1989 Molecular cloning of Saccharomyces cerevisiae CDC6 gene. Isolation, identification, and sequence analysis. The Journal of biological chemistry 55 2656692
2020 Cdc6 as a novel target in cancer: Oncogenic potential, senescence and subcellular localisation. International journal of cancer 53 32010971
2020 Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6. Proceedings of the National Academy of Sciences of the United States of America 53 32669428
2008 Expression of Mcm7 and Cdc6 in oral squamous cell carcinoma and precancerous lesions. Anticancer research 51 19189662
2021 UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications. Cancer letters 49 34265399
1999 The Cdc6 protein is ubiquitinated in vivo for proteolysis in Saccharomyces cerevisiae. The Journal of biological chemistry 49 10085159
2021 Multiple, short protein binding motifs in ORC1 and CDC6 control the initiation of DNA replication. Molecular cell 48 33761311
2020 ZNF143-Mediated H3K9 Trimethylation Upregulates CDC6 by Activating MDIG in Hepatocellular Carcinoma. Cancer research 48 32312832
2016 Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells. Oncotarget 48 27246979
1990 CDC6 mRNA fluctuates periodically in the yeast cell cycle. The Journal of biological chemistry 48 2246267
2018 Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition. Oncogene 47 30158672
2002 Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. Molecular biology of the cell 45 12429841
2000 The stability of the Cdc6 protein is regulated by cyclin-dependent kinase/cyclin B complexes in Saccharomyces cerevisiae. The Journal of biological chemistry 45 10734126
2009 Cdc6 and cyclin E2 are PTEN-regulated genes associated with human prostate cancer metastasis. Neoplasia (New York, N.Y.) 44 19107233
2019 The RNA-Binding Protein HuR Confers Oxaliplatin Resistance of Colorectal Cancer By Upregulating CDC6. Molecular cancer therapeutics 43 31064870
2021 The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6. Nature communications 42 34162887
2005 Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 42 15696126
2003 Genetic and biochemical evaluation of the importance of Cdc6 in regulating mitotic exit. Molecular biology of the cell 42 12960422
2004 CDC6 requirement for spindle formation during maturation of mouse oocytes. Biology of reproduction 40 15385409
2003 Biochemical characterization of a CDC6-like protein from the crenarchaeon Sulfolobus solfataricus. The Journal of biological chemistry 40 12966100
2002 Cdc6 synthesis regulates replication competence in Xenopus oocytes. Nature 39 12384699
2016 WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck. Oncotarget 38 27285764
2006 Norcantharidin inhibits DNA replication and induces apoptosis with the cleavage of initiation protein Cdc6 in HL-60 cells. Anti-cancer drugs 38 16520659
2020 Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6. Nature communications 37 32848132
2017 DNA replication licensing factor Cdc6 and Plk4 kinase antagonistically regulate centrosome duplication via Sas-6. Nature communications 37 28447620
2008 Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage. The Journal of biological chemistry 37 18617514
2001 Cdc6 expression as a marker of proliferative activity in brain tumors. Oncology reports 37 11496317
2014 FOXM1 and androgen receptor co-regulate CDC6 gene transcription and DNA replication in prostate cancer cells. Biochimica et biophysica acta 36 24583551
2005 Androgen receptor regulates Cdc6 in synchronized LNCaP cells progressing from G1 to S phase. Journal of cellular physiology 36 15887248
2002 Human replication protein Cdc6 is selectively cleaved by caspase 3 during apoptosis. EMBO reports 36 12151338
1988 Cloning and characterization of the Saccharomyces cerevisiae CDC6 gene. Nucleic acids research 36 3062576
2018 Mir-26b inhibits growth and resistance to paclitaxel chemotherapy by silencing the CDC6 gene in gastric cancer. Archives of medical science : AMS 33 30899303
1999 The RLF-B component of the replication licensing system is distinct from Cdc6 and functions after Cdc6 binds to chromatin. Current biology : CB 33 10074431
2018 An Orc1/Cdc6 ortholog functions as a key regulator in the DNA damage response in Archaea. Nucleic acids research 32 29878182
2014 PIP-box-mediated degradation prohibits re-accumulation of Cdc6 during S phase. Journal of cell science 32 24434580
2009 Archaeal eukaryote-like Orc1/Cdc6 initiators physically interact with DNA polymerase B1 and regulate its functions. Proceedings of the National Academy of Sciences of the United States of America 31 19416914
2015 Cdc6 ATPase activity disengages Cdc6 from the pre-replicative complex to promote DNA replication. eLife 29 26305410
2013 The ORC/Cdc6/MCM2-7 complex facilitates MCM2-7 dimerization during prereplicative complex formation. Nucleic acids research 29 24234446
2007 Genomewide and biochemical analyses of DNA-binding activity of Cdc6/Orc1 and Mcm proteins in Pyrococcus sp. Nucleic acids research 29 17452353
2006 Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. The Journal of cell biology 29 16801388
2008 Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. Biochimica et biophysica acta 28 18541154
2002 Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix. Archives of pathology & laboratory medicine 28 12296751
2008 The human TPR protein TTC4 is a putative Hsp90 co-chaperone which interacts with CDC6 and shows alterations in transformed cells. PloS one 27 18320024
2002 Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer. The Journal of biological chemistry 27 12006585
2016 Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. eLife 26 27458800
2003 Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis. Molecular biology of the cell 26 14517333
2019 Downregulation of Cdc6 inhibits tumorigenesis of osteosarcoma in vivo and in vitro. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 31100539
2018 CDC6 mRNA Expression Is Associated with the Aggressiveness of Prostate Cancer. Journal of Korean medical science 25 30450027
2012 A yeast GSK-3 kinase Mck1 promotes Cdc6 degradation to inhibit DNA re-replication. PLoS genetics 25 23236290
2022 LCAT1 is an oncogenic LncRNA by stabilizing the IGF2BP2-CDC6 axis. Cell death & disease 24 36257938
2012 Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules. The Journal of biological chemistry 24 22493447
2007 Cdc18/CDC6 activates the Rad3-dependent checkpoint in the fission yeast. Nucleic acids research 23 17690116
2003 Down to the origin: Cdc6 protein and the competence to replicate. Trends in cell biology 23 12628342
2017 Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype. Human molecular genetics 22 28985365
1995 The genomic instability of yeast cdc6-1/cdc6-1 mutants involves chromosome structure and recombination. Molecular & general genetics : MGG 21 8552037
2024 Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance. Molecular cancer 20 38685067
2020 Cdc6 disruption leads to centrosome abnormalities and chromosome instability in pancreatic cancer cells. Scientific reports 20 33020506

Missed literature

Know a paper Affinage missed for CDC6? Flag it for the maintainers and the community.

No submissions yet.