Affinage

CDC7

Cell division cycle 7-related protein kinase · UniProt O00311

Length
574 aa
Mass
63.9 kDa
Annotated
2026-06-09
100 papers in source corpus 53 papers cited in narrative 50 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC7 is a conserved cell-cycle-regulated serine/threonine protein kinase that drives initiation of DNA replication by phosphorylating the MCM2-7 replicative helicase, and its essential activity depends on binding a cyclin-like regulatory activator (PMID:2166954, PMID:8474449, PMID:9407029). Activity is contributed by a dedicated activator subunit—Dbf4/ASK in budding yeast and human, with the alternative regulators Drf1 and developmentally regulated activator switching in vertebrates—that wraps around CDC7 and stabilizes its αC helix to switch on the kinase, while also docking the complex onto MCM2 and replication origins (PMID:8474449, PMID:8066465, PMID:10373557, PMID:12065429, PMID:16204181, PMID:23064647). Within the pre-replication complex CDC7-DBF4 (DDK) phosphorylates the N-terminal domains of MCM2, MCM4 and other MCM subunits at sites whose creation is often primed by prior CDK phosphorylation, and its sole essential function is to relieve the inhibitory MCM4 N-terminal serine/threonine-rich domain (NSD) to license origin firing throughout S phase; cryo-EM shows DBF4 bridges the MCM double hexamer and displaces the MCM4 NSD to position CDC7 for trans-hexamer phosphorylation (PMID:9407029, PMID:9472017, PMID:9472018, PMID:16864800, PMID:17046832, PMID:20054399, PMID:21070963, PMID:35614055, PMID:35296675). These phosphorylations license loading of CDC45 and GINS to fire both early and late origins and are reversed by Rif1-directed PP1, establishing a phospho-switch controlling origin activation (PMID:11005825, PMID:20054399, PMID:24532715, PMID:29123096). Beyond core initiation, CDC7 couples replication to chromatin assembly, cohesion, and checkpoint signaling—phosphorylating CAF1-p150, recruiting the Scc2-Scc4 cohesin loader, phosphorylating Claspin to activate ATR-Chk1, and acting at stalled forks to promote MRE11-dependent fork processing (PMID:16826239, PMID:18084324, PMID:18628396, PMID:23746350, PMID:27401717, PMID:31889509, PMID:32496651). In meiosis DDK phosphorylates Mer2, Rec8 and the monopolin subunit Lrs4 to control double-strand break formation, cohesin cleavage, and reductional chromosome segregation (PMID:18245450, PMID:18245451, PMID:19013276, PMID:20230747). Its activity is gated by allosteric ADP product feedback relieved by nuclear PGK1 and by ATR-Chk1 control of activator stability, and in mammalian cells CDC7 functions redundantly with CDK1 at the G1/S transition; CDC7 also directly phosphorylates TDP-43 at pathological residues linked to neurodegeneration (PMID:23424178, PMID:24240236, PMID:30392930, PMID:35508654).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1990 High

    Established that the CDC7 gene product is itself a protein kinase, resolving whether CDC7 acted directly or via a downstream enzyme.

    Evidence Immunoprecipitation kinase assay with thermolabile cdc7-1 ts-mutant extracts in yeast

    PMID:2166954

    Open questions at the time
    • Physiological substrates not identified
    • Regulation of kinase activity unknown
  2. 1991 High

    Showed catalytic activity is required for both mitotic replication and meiotic functions, linking one enzymatic activity to dual cell-cycle roles.

    Evidence Active-site mutagenesis with mitotic and meiotic complementation readouts in yeast

    PMID:1865880

    Open questions at the time
    • Distinct substrates for mitotic vs meiotic roles not defined
  3. 1993 High

    Identified Dbf4 as a cyclin-like activator subunit and established cell-cycle-regulated activation peaking at G1/S, defining CDC7 as a regulated heterodimeric kinase.

    Evidence In vitro reconstitution, two-hybrid, cell-cycle synchronization kinase assays, plus phosphatase/phosphopeptide analysis of Cdc28-dependent activation

    PMID:8382976 PMID:8474449

    Open questions at the time
    • Direct substrates at origins not yet known
    • Mechanism of Dbf4 activation structurally undefined
  4. 1994 Medium

    Connected the kinase to replication origins by showing Dbf4 binds origins, framing the activator as the targeting subunit.

    Evidence Two-hybrid and one-hybrid in vivo interaction assays in yeast

    PMID:8066465

    Open questions at the time
    • Direct origin binding vs indirect recruitment not distinguished
    • No biochemical reconstitution of origin docking
  5. 1995 High

    Demonstrated conservation of the essential replication-initiation function via the fission yeast ortholog Hsk1.

    Evidence Gene disruption and DNA content analysis of germinating spores

    PMID:7621824

    Open questions at the time
    • Substrate conservation not directly tested in this study
  6. 1997 High

    Identified MCM2-7 subunits as direct CDC7-Dbf4 substrates and placed the kinase genetically upstream of Mcm2, defining the core substrate of replication initiation.

    Evidence Genetic suppressor screen, in vitro kinase assay, Co-IP, and cell-cycle block in yeast, plus cloning of human/Xenopus orthologs phosphorylating MCM2/3

    PMID:9250678 PMID:9407029

    Open questions at the time
    • Functional consequence of MCM phosphorylation not yet defined
    • Specific phospho-sites unmapped
  7. 1998 High

    Established that CDC7 acts throughout S phase to fire successive origins, not only for S-phase entry, revealing continuous origin-firing control.

    Evidence Temperature-sensitive cdc7 allele with 2D-gel analysis of replication intermediates

    PMID:9472017 PMID:9472018

    Open questions at the time
    • Molecular trigger distinguishing early vs late origins unresolved
  8. 1999 High

    Reconstituted the human kinase, validated MCM2 as its in vivo substrate, and showed it is essential for human replication initiation, plus identified ASK as the human activator.

    Evidence Co-expression reconstitution, 2D phosphopeptide mapping, antibody microinjection in HeLa, immunodepletion, and chromatin-association analysis in yeast

    PMID:10373557 PMID:10465792 PMID:10523313

    Open questions at the time
    • In vivo functional MCM phospho-sites not mapped
    • How chromatin recruitment is achieved mechanistically unclear
  9. 2000 High

    Ordered DDK relative to CDK and downstream of MCM loading, and identified Cdc45 loading and Thr-376 CDK priming, establishing the CDK→DDK→Cdc45 hierarchy.

    Evidence Xenopus egg extract chromatin fractionation with order-of-addition experiments, in vitro phosphorylation, and Thr-376 mutagenesis

    PMID:10805723 PMID:10846177 PMID:10859170 PMID:11005825

    Open questions at the time
    • Whether Cdc45 is a direct essential DDK substrate vs MCM phosphorylation acting upstream not fully resolved
  10. 2001 High

    Dissected Dbf4 into modular motifs, showing bipartite activation and a separable checkpoint/origin function, clarifying how the activator both switches on and targets the kinase.

    Evidence In vitro kinase assays with truncation/fusion constructs and complementation in fission yeast

    PMID:11402029

    Open questions at the time
    • Structural basis of motif-mediated activation not yet visualized
  11. 2002 High

    Defined mammalian CDC7 as essential for ongoing DNA synthesis with a p53-dependent apoptotic response, and revealed an alternative activator Drf1.

    Evidence Conditional Cdc7 knockout in mouse ES cells with Rad51/p53 readouts, plus Co-IP and kinase assays identifying Drf1

    PMID:11980714 PMID:12065429

    Open questions at the time
    • Functional division of labor between Dbf4 and Drf1 unresolved
    • Mechanism linking Cdc7 loss to p53 activation undefined
  12. 2003 High

    Placed CDC7-Dbf4 activity within the ATR-controlled replication checkpoint that blocks initiation upon DNA damage.

    Evidence Xenopus egg extract assay with ATR immunodepletion and Cdc45 chromatin loading readouts

    PMID:12535533

    Open questions at the time
    • Direct molecular target of checkpoint inhibition of DDK not identified here
  13. 2004 High

    Revealed a p53-dependent checkpoint that distinguishes normal from cancer cells upon CDC7 loss, establishing the basis for cancer-selective CDC7 targeting.

    Evidence siRNA knockdown with flow cytometry and p53 functional analysis in fibroblasts vs cancer cells

    PMID:15466207

    Open questions at the time
    • Molecular nature of the checkpoint sensing CDC7 loss undefined
  14. 2005 High

    Showed developmentally regulated switching between Cdc7-Drf1 and Cdc7-Dbf4, explaining context-specific activator usage.

    Evidence Xenopus immunodepletion with developmental staging and Mcm4 phosphorylation kinase assays

    PMID:16204181

    Open questions at the time
    • Mechanism controlling the developmental Drf1-to-Dbf4 switch unknown
  15. 2006 High

    Mapped CDC7 phosphorylation motifs on MCM2/MCM4 N-termini, demonstrated CDK priming, and linked MCM4 phosphorylation to Cdc45 loading, plus extended substrates to CAF1-p150 for chromatin assembly.

    Evidence In vitro phosphorylation with peptide mutagenesis, Cdc7-KO mouse ES cells, phospho-specific antibodies, and PCNA-loading assays

    PMID:16826239 PMID:16864800 PMID:17046832 PMID:17062569

    Open questions at the time
    • Relative contribution of individual phospho-sites to origin firing not quantified
    • Whether CAF1 phosphorylation is essential in vivo untested
  16. 2007 High

    Connected CDC7 to checkpoint activation through Claspin phosphorylation enabling Chk1 activation, and showed reciprocal Chk1-Dbf4 regulation.

    Evidence Co-IP, in vitro kinase assays, Cdc7-KO ES cells, and overexpression checkpoint assays

    PMID:17276990 PMID:18084324

    Open questions at the time
    • Precise Claspin sites phosphorylated by Cdc7 not yet mapped here
    • Chk1-Dbf4 interaction only weakly detected
  17. 2008 High

    Established meiosis-specific DDK functions—Mer2 phosphorylation for DSB formation, Lrs4/monopolin recruitment for monopolar attachment, and cohesin loader tethering—broadening CDC7 beyond replication.

    Evidence Analog-sensitive Cdc7 chemical genetics with ChIP, mutagenesis, imaging in yeast, and Xenopus DDK-Scc2/Scc4 immunodepletion/rescue

    PMID:18245450 PMID:18245451 PMID:18628396 PMID:18768747 PMID:19013276

    Open questions at the time
    • Whether cohesin-loader recruitment uses a phospho-target or scaffolding role not fully defined
  18. 2009 High

    Defined the molecular logic of DDK-MCM docking—Dbf4 binds Mcm2 to recruit Cdc7—and identified essential Mcm2 phospho-sites via DDK-bypass genetics.

    Evidence Biochemical pulldowns, site-directed in vitro kinase assays, and mcm5-bob1 bypass genetics in yeast, plus LEDGF as an activating interactor

    PMID:19692334 PMID:19864417

    Open questions at the time
    • In vivo role of LEDGF stimulation of human Cdc7 untested in replication
    • Structural basis of docking not resolved here
  19. 2010 High

    Identified the MCM4 NSD as the essential DDK target, defining relief of NSD inhibition as the sole essential function, and mapped the priming-kinase requirement.

    Evidence Genetic NSD deletion/point mutation and phosphomimetic DDK-bypass genetics in yeast, plus Mec1/Mrc1 priming analysis and Rec8 phospho-analysis

    PMID:20054399 PMID:20230747 PMID:21070963

    Open questions at the time
    • How NSD inhibition mechanistically blocks initiation not structurally defined at the time
  20. 2012 High

    Provided the crystal structure of human CDC7-DBF4, revealing how DBF4 wraps and activates the kinase and how inhibitors bind, enabling structure-guided understanding of activation.

    Evidence X-ray crystallography of active and inhibitor-bound human complexes

    PMID:23064647

    Open questions at the time
    • Substrate-bound and MCM-engaged conformations not captured
  21. 2013 High

    Expanded CDC7 functions to kinetochore-localized origin/cohesion control, replication-stress activator stabilization, and a non-replication role phosphorylating TDP-43 in neurodegeneration.

    Evidence ChIP-seq/imaging/epistasis in yeast, ATR-Chk1/APC-Cdh1 and RAD18 Co-IP studies, and C. elegans/cell-culture/inhibitor TDP-43 assays, plus DDK-MCM docking-interface mapping

    PMID:23424178 PMID:23549044 PMID:23746350 PMID:24240236

    Open questions at the time
    • Whether TDP-43 is a physiological CDC7 substrate beyond pathology unclear
    • Mechanism of kinetochore recruitment of DDK only partly defined
  22. 2014 High

    Identified Rif1-PP1 as the phosphatase that reverses DDK-mediated MCM4 phosphorylation, establishing a phospho-switch with feedback on Rif1 itself.

    Evidence Co-IP, phosphorylation assays, and genetic epistasis in cdc7-1 yeast

    PMID:24532715

    Open questions at the time
    • Spatial/temporal control of the Rif1-PP1 vs DDK balance at individual origins unresolved
  23. 2016 High

    Revealed Claspin as a recruiter of CDC7 to origins via an acidic patch, coupling checkpoint scaffolding to MCM phosphorylation.

    Evidence Conditional Claspin-KO MEF rescue with Co-IP and MCM phosphorylation assays

    PMID:27401717

    Open questions at the time
    • Relative contribution of Claspin- vs Dbf4-mediated recruitment not quantified
  24. 2017 Medium

    Implicated CDC7 in unscheduled origin firing under ATR inhibition through phosphorylation of GINS subunits.

    Evidence Phosphoproteomics and Co-IP with CDC7 inhibitor treatment

    PMID:29123096

    Open questions at the time
    • Direct GINS phospho-sites not mapped
    • Single lab, limited orthogonal validation
  25. 2018 High

    Uncovered allosteric ADP product-feedback inhibition of CDC7 and its relief by nuclear PGK1 under growth-factor signaling, linking metabolism to replication initiation.

    Evidence In vitro kinase/ADP-binding assays, Co-IP, CK2α phosphorylation, and chromatin fractionation

    PMID:30392930

    Open questions at the time
    • In vivo importance of PGK1 control across cell types not established
  26. 2019 High

    Explained cancer-selective CDC7 dependency by showing Cdc7 phosphorylates the Claspin Chk1-binding domain in cancer cells whereas CK1γ1 substitutes in normal cells.

    Evidence Conditional Cdc7 KO, siRNA double-depletion, Co-IP, and in vitro kinase assays

    PMID:31889509

    Open questions at the time
    • Determinants of cancer-cell switch from CK1γ1 to Cdc7 unknown
  27. 2020 High

    Placed CDC7 at replication forks driving MRE11-dependent fork processing and pathological degradation in BRCA2-deficient cells, extending its role to fork stability.

    Evidence Chemical-genetic CDC7 inhibition with DNA fiber analysis, EM of replication intermediates, and MRE11 localization

    PMID:32496651

    Open questions at the time
    • Direct CDC7 substrate driving MRE11 recruitment not identified
  28. 2022 High

    Resolved the trans-hexamer mechanism of DDK action by cryo-EM and demonstrated CDC7-CDK1 functional redundancy at G1/S, redefining the mammalian requirement for CDC7.

    Evidence Cryo-EM of yeast DDK-MCM double hexamer with mutagenesis, plus degron-tagged CDC7 with CDK1 inhibition in cells and mice

    PMID:35296675 PMID:35508654 PMID:35614055

    Open questions at the time
    • Whether mammalian DDK uses the same trans-hexamer mechanism structurally untested
    • Tissue contexts where CDC7 is strictly non-redundant not fully delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple non-replication CDC7 substrates (Claspin, MRE11 pathway, GINS, CAF1, meiotic targets) are spatially and temporally coordinated with core MCM phosphorylation in human cells, and which functions underlie therapeutic CDC7 inhibition, remains unresolved.
  • Integration of replication, checkpoint, cohesion, and fork-protection roles in a single mammalian system undefined
  • Structural basis of human DDK-MCM engagement and substrate selection not established
  • In vivo substrate hierarchy underlying cancer-selective lethality unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 6 GO:0098772 molecular function regulator activity 5 GO:0140657 ATP-dependent activity 2
Localization
GO:0000228 nuclear chromosome 6 GO:0005634 nucleus 1
Pathway
R-HSA-69306 DNA Replication 6 R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-1474165 Reproduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-73894 DNA Repair 2 R-HSA-4839726 Chromatin organization 1
Partners
CLSPNDBF4DRF1LEDGFMCM2MCM4PGK1SCC2
Complex memberships
CDC7-DBF4/ASK (DDK)CDC7-DRF1

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 CDC7 encodes a serine/threonine protein kinase; immune complexes phosphorylate histone H1, and kinase activity is thermolabile in cdc7-1 temperature-sensitive mutant extracts, confirming the kinase is the CDC7 gene product. Immunoprecipitation kinase assay, temperature-sensitive mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 2166954
1991 CDC7 protein kinase activity (requiring conserved catalytic residues) is essential for both mitotic DNA replication initiation and meiotic functions; catalytic domain mutations abolish both activities. Site-directed mutagenesis of catalytic residues, complementation assay in yeast Molecular & general genetics : MGG High 1865880
1993 Cdc7 kinase activity is cell-cycle regulated (maximal at G1/S), requires the Dbf4 protein for activity, and Cdc7 and Dbf4 interact physically both in vitro and in vivo; Dbf4 functions as a cyclin-like activator of Cdc7. In vitro reconstitution, two-hybrid protein interaction assay, cell-cycle synchronization kinase assay, thermolabile dbf4 mutant extracts Molecular and cellular biology High 8474449
1993 Cdc7 kinase activity oscillates through the cell cycle and is activated by phosphorylation; dephosphorylation destroys activity, and phosphorylation by Cdc28 kinase contributes to Cdc7 activation. Phosphatase treatment of immunoprecipitates, phosphopeptide mapping, thermolabile cdc28 mutant extracts Molecular biology of the cell Medium 8382976
1994 Dbf4 protein interacts with yeast replication origins in vivo, and this origin-binding activity suggests Dbf4 recruits Cdc7 kinase to initiation complexes at replication origins. Two-hybrid and one-hybrid in vivo interaction assays Science (New York, N.Y.) Medium 8066465
1995 Hsk1, the fission yeast Cdc7 ortholog, is essential for chromosomal DNA replication; gene disruption causes lethality with blocked DNA replication, demonstrating conservation of the replication initiation function. Gene disruption, DNA content analysis of germinating spores The EMBO journal High 7621824
1997 Cdc7-Dbf4 physically interacts with Mcm2 and phosphorylates Mcm2 and three other MCM2-7 family members (Mcm3, Mcm4, Mcm7) in vitro; blocking Cdc7-Dbf4 activity at G1/S prevents Mcm2 phosphorylation in vivo. A dbf4 suppressor mutation of mcm2-1 establishes genetic epistasis placing Cdc7-Dbf4 and Mcm2 in the same pathway. Genetic suppressor screen, in vitro kinase assay, co-immunoprecipitation, cell-cycle block experiments Genes & development High 9407029
1997 Human Cdc7 (huCdc7) and Xenopus Cdc7 (xeCdc7) are functional orthologs of yeast Cdc7; huCdc7 expressed in COS7 cells phosphorylates MCM2 and MCM3 in vitro, indicating conservation of MCM-targeting function. cDNA cloning, in vitro kinase assay with recombinant protein The EMBO journal Medium 9250678
1998 Cdc7 is required throughout S phase for sequential activation of early- and late-firing replication origins, not merely for S-phase entry; partial loss of Cdc7 function selectively blocks late origin firing after a hydroxyurea arrest. Temperature-sensitive cdc7 allele, 2D gel electrophoresis of replication intermediates, DNA content analysis Genes & development High 9472017 9472018
1999 Human Cdc7 (HsCdc7) forms a complex with its regulatory subunit HsDbf4; HsDbf4 activates HsCdc7 kinase activity; the complex selectively phosphorylates MCM2 within the MCM complex in vitro; in vivo MCM2 phosphopeptides comigrate with those phosphorylated by HsCdc7-HsDbf4; microinjection of anti-HsCdc7 antibodies blocks initiation of DNA replication in HeLa cells. Co-expression in insect/mammalian cells, in vitro kinase assay, 2D tryptic phosphopeptide mapping, antibody microinjection The EMBO journal High 10523313
1999 ASK (activator of S-phase kinase, the human Dbf4 homolog) binds and activates huCdc7 kinase; immunodepletion of ASK abolishes huCdc7-dependent kinase activity; microinjection of ASK-specific antibodies blocks DNA replication; ASK expression oscillates through the cell cycle, peaking in S phase. Co-immunoprecipitation, immunodepletion, antibody microinjection, cell-cycle synchronization Molecular and cellular biology High 10373557
1999 Dbf4 protein accumulates on chromatin in late G1 in a punctate pattern dependent on ORC but not Cdc6 or Clb/Cdc28 activity; the Dbf4/Cdc7 kinase complex must be provided by template nuclei (not added in trans) for replication initiation in a reconstituted yeast in vitro system. Reconstituted yeast in vitro replication assay, chromatin fractionation, immunofluorescence Genes & development High 10465792
2000 Xenopus Cdc7 (XCdc7) binds to chromatin after origin licensing (MCM loading) but independently of ORC/Cdc6 continued presence; XCdc7 is required for CDK-dependent loading of XCdc45 onto chromatin but does not require CDK activity itself for chromatin association or MCM phosphorylation. Xenopus egg extract system, immunodepletion, chromatin fractionation Genes & development High 10859170
2000 In Xenopus egg extracts, Cdc7 enriched in nucleoplasm binds chromatin at G1/S in an MCM-dependent manner, is required for Cdc45 loading, and efficient replication requires Cdc7 action before Cdk2 (sequential order established). Xenopus cell-free replication system, chromatin fractionation, order-of-addition experiments The Journal of biological chemistry High 11005825
2000 Human CDC7 kinase (huCdc7-ASK) phosphorylates MCM2 (and to a lesser extent MCM4 and MCM6) in vitro; prior CDK phosphorylation of the MCM2-4-6-7 complex facilitates subsequent huCdc7 phosphorylation; Thr-376 of huCdc7 (activating threonine) is phosphorylated by Cdk2-Cyclin E/A and Cdc2-Cyclin B, and its mutation to alanine dramatically reduces kinase activity. Purified baculovirus-expressed kinase, in vitro phosphorylation assay, site-directed mutagenesis The Journal of biological chemistry High 10846177
2000 DDK (Dbf4-Cdc7) activity is cell cycle regulated and peaks during S phase; DDK can perform its replication function only after S-CDK activation (hierarchical dependency); Cdc45 is phosphorylated by DDK in vitro, suggesting it is a critical DDK substrate downstream of CDK. Cell-cycle synchronization kinase assay, in vitro phosphorylation, genetic epistasis Molecular and cellular biology Medium 10805723
2001 Dbf4 motifs M (proline-rich) and C (zinc-finger) each independently bind to and partially activate Hsk1 (fission yeast Cdc7 ortholog); co-expression of both motifs or a fusion construct activates Hsk1 fully (bipartite activation mechanism). Motif N (BRCA-CT-like) is dispensable for mitotic functions but required for checkpoint responses and origin interaction. In vitro kinase assay with truncation mutants, co-expression, yeast complementation assay The Journal of biological chemistry High 11402029
2002 Inactivation of murine Cdc7 (muCdc7) in mouse ES cells causes rapid cessation of DNA synthesis within S phase, generating Rad51 foci (recombinational repair) and p53-dependent apoptosis; inhibition of p53 partially rescues cell viability, establishing Cdc7 as essential for ongoing DNA synthesis and positioning p53 as a downstream effector. Conditional gene knockout (Cre-loxP), DNA content analysis, immunofluorescence for Rad51, p53 inhibition rescue The EMBO journal High 11980714
2002 A novel human Cdc7 regulatory subunit, Drf1, binds to Cdc7 and activates its kinase activity; Drf1 is nuclear, cell-cycle regulated, and is distinct from ASK/Dbf4, establishing that human Cdc7 can be activated by two alternative regulatory subunits. Co-immunoprecipitation, in vitro kinase assay, immunofluorescence The EMBO journal High 12065429
2003 ATR (not ATM) and Cdc7/Dbf4 kinase activity are required for a DNA damage checkpoint that blocks initiation of DNA replication in Xenopus egg extracts; single-strand DNA gaps activate this checkpoint, and inhibition results in failure of Cdc45 to bind chromatin. Checkpoint does not require pre-RC assembly but requires RPA loading. Xenopus egg extract assay, caffeine inhibition, immunodepletion of ATR, kinase activity measurement Molecular cell High 12535533
2004 In normal (non-cancer) human fibroblasts, depletion of Cdc7 by siRNA activates a p53-dependent checkpoint that prevents progression through a lethal S phase; cancer cells lacking this checkpoint undergo abortive S phase and apoptosis. p53 is required for lasting maintenance of the Cdc7-depletion checkpoint. siRNA knockdown, flow cytometry, p53 functional analysis Cancer research High 15466207
2005 In Xenopus egg extracts, Cdc7-Drf1 (not Cdc7-Dbf4) is the predominant active complex and is required for Mcm4 phosphorylation and DNA replication; after gastrulation, Drf1 levels decline and Cdc7-Dbf4 becomes dominant, establishing developmentally regulated switching of activator subunits. Xenopus immunodepletion, immunoblot, in vitro kinase assay, developmental staging Genes & development High 16204181
2006 Human CDC7 kinase phosphorylates MCM2 at two major N-terminal sites (Ser-5 and Ser-53) and three minor sites; phosphorylation requires an acidic residue adjacent to the serine; a CDK-primed phospho-Ser-27 can create an additional Cdc7 site on MCM2, explaining sequential CDK-Cdc7 action. In vitro kinase assay with truncated MCM2 peptides, alanine substitution, synthetic phosphopeptides Proceedings of the National Academy of Sciences of the United States of America High 16864800
2006 Cdc7 phosphorylates the N-terminal domain of MCM4 in S phase on chromatin; S phase-specific MCM4 phosphorylation at (S/T)(S/T)P motifs is Cdc7-dependent (absent in Cdc7-knockout mouse ES cells); MCM4 N-terminal phosphorylation stimulates chromatin association of Cdc45. Cdc7 conditional knockout mouse ES cells, siRNA knockdown, phospho-amino acid antibodies, co-immunoprecipitation, SDS-PAGE mobility shift The Journal of biological chemistry High 17046832
2006 Cdc7-Dbf4 kinase directly phosphorylates the p150 subunit of CAF1 (chromatin assembly factor 1); this phosphorylation changes p150 oligomerization state, promoting its binding to PCNA; Cdc7 depletion reduces CAF1 recruitment in a PCNA/DNA loading assay, linking replication initiation to chromatin assembly. Co-immunoprecipitation (S-phase specific), in vitro kinase assay, PCNA-loading assay, immunodepletion EMBO reports High 16826239
2006 Human Cdc7·Dbf4 and Cdc7·Drf1 kinase complexes remain active and stable during replication stress (hydroxyurea, etoposide); Cdc7 depletion impairs Mcm2 and Mcm4 phosphorylation at Cdc7-dependent sites under these conditions, supporting an active role for Cdc7 during replication stress. Co-immunoprecipitation, chromatin fractionation, siRNA knockdown, phospho-specific antibody immunoblot The Journal of biological chemistry Medium 17062569
2007 Cdc7 kinase interacts with and phosphorylates Claspin; Cdc7 deletion in mouse ES cells or siRNA depletion abrogates HU- or UV-induced Chk1 activation, while ATR and Rad17 still relocate to chromatin normally; Cdc7-depleted cells show defects in Claspin chromatin association and phosphorylation. Co-immunoprecipitation, in vitro kinase assay, Cdc7 conditional KO mouse ES cells, siRNA knockdown, immunofluorescence Oncogene High 18084324
2007 Dbf4 interacts with Chk1 in vivo (weak interaction) and is a substrate for Chk1-dependent phosphorylation in vitro; overexpression of Dbf4 abrogates the S-checkpoint response to UVC but not ionizing radiation, implicating Dbf4-Cdc7 as a target of the ATR-Chk1 S-checkpoint pathway. Co-immunoprecipitation, in vitro kinase assay (Chk1 on Dbf4), overexpression with checkpoint assay The Journal of biological chemistry Medium 17276990
2008 Cdc7-Dbf4 (DDK) in yeast promotes meiotic double-strand break (DSB) formation by phosphorylating Mer2 (a Spo11 co-activator) at Ser-29, which requires prior CDK phosphorylation of Ser-30 as a priming event. This DDK-dependent Mer2 phosphorylation facilitates chromatin binding of Spo11, Rec114, and Mei4. Chemical genetics (analog-sensitive Cdc7), site-directed mutagenesis of Mer2, chromatin immunoprecipitation, genetic analysis Genes & development High 18245450 18245451
2008 DDK (Cdc7-Dbf4) in yeast promotes monopolin complex recruitment to kinetochores (required for monopolar attachment at meiosis I) through phosphorylation of the monopolin subunit Lrs4, acting together with polo-kinase Cdc5-Spo13; DDK is thus required for reductional chromosome segregation at meiosis I. Chemical genetics (analog-sensitive cdc7), phosphorylation assay, live-cell imaging, genetic epistasis Cell High 19013276
2008 Cdc7-Drf1 (DDK) in Xenopus egg extracts is required to tether the Scc2-Scc4 cohesin loader to pre-RCs; DDK and Scc2-Scc4 form a stable complex; immunodepletion of DDK impairs Scc2-Scc4 chromatin association, and this defect requires catalytically active DDK to rescue. Co-immunoprecipitation, immunodepletion in Xenopus extract, chromatin fractionation, kinase-dead DDK rescue Genes & development High 18628396
2008 Cdc7-Dbf4 (DDK) regulates NDT80 transcription (a meiotic transcription factor) and monopolin recruitment to kinetochores for reductional segregation at meiosis I in budding yeast, functions beyond its role in premeiotic DNA replication. Chemical genetics (analog-sensitive Cdc7), fluorescence microscopy of kinetochores, gene expression analysis Molecular biology of the cell Medium 18768747
2009 Dbf4 alone binds tightly to Mcm2 and recruits Cdc7 (which binds Mcm2 weakly alone) to phosphorylate Mcm2 at Ser-164 and Ser-170; mcm2-S170A is lethal in MCM2 null yeast but rescued by the DDK-bypass mutation mcm5-bob1, placing Mcm2-S170 phosphorylation as an essential DDK target for cell growth. Biochemical pulldown, in vitro kinase assay with site-directed mutants, yeast genetics/complementation The Journal of biological chemistry High 19692334
2009 LEDGF interacts with the Cdc7-ASK heterodimer through its integrase-binding domain; the interaction requires kinase autophosphorylation and 50 C-terminal residues of ASK; LEDGF stimulates Cdc7-ASK kinase activity >10-fold in vitro by relieving ASK C-terminus-mediated autoinhibition; Cdc7 phosphorylates LEDGF at Ser-206 during S phase. Co-immunoprecipitation from human cell extracts, truncation mutagenesis, in vitro kinase assay, mass spectrometry The Journal of biological chemistry High 19864417
2010 The N-terminal serine/threonine-rich domain (NSD) of Mcm4 contains both inhibitory and facilitating regulatory elements; the sole essential function of DDK (Cdc7-Dbf4) is to relieve the inhibitory activity of the Mcm4 NSD to promote DNA replication initiation. CDK phosphorylation of the distal Mcm4 NSD becomes crucial in absence of DDK. Genetic deletion and point mutation of MCM4 NSD, cell-cycle analysis, hydroxyurea sensitivity assay Nature High 20054399
2010 Mec1 (ATR ortholog) is one of multiple kinases that prime the Mcm2-7 helicase with S/T-P or S/T-Q phosphorylations, which are required for subsequent DDK phosphorylation of Mcm2-7; Mrc1 facilitates Mec1 phosphorylation of Mcm2-7 during S phase; phosphomimetic mutations at DDK target sites bypass DDK function. In vitro kinase assay, site-directed mutagenesis, phosphomimetic bypass genetics, genetic interaction analysis Molecular cell High 21070963
2010 Rec8 phosphorylation by both casein kinase 1δ/ε (CK1δ/ε) and DDK (Cdc7-Dbf4) at multiple sites is required for Rec8 cleavage by separase during meiosis I; phosphomimetic Rec8 mutations bypass centromeric protection and are cleaved even when both kinases are inhibited, establishing that phosphorylation is sufficient for separase cleavage. Chemical-genetic and small-molecule kinase inhibition, phosphomimetic mutagenesis, meiotic chromosome segregation assay Developmental cell High 20230747
2012 Crystal structure of human CDC7-DBF4 complex reveals that DBF4 wraps around CDC7, burying ~6,000 Ų of hydrophobic surface; DBF4 motif C (effector domain) stabilizes the CDC7 αC helix to activate the kinase; motif M tethers to the CDC7 C-terminal lobe; structures of both active and ATP-competitor-inhibited forms are presented. X-ray crystallography, structure-function analysis with small molecule inhibitor complexes Nature structural & molecular biology High 23064647
2013 CDC7 directly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture; PHA767491 (CDC7 inhibitor) reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43 transgenic animals. RNAi kinase screen in C. elegans, in vitro kinase assay, human cell culture phosphorylation assay, pharmacological inhibition with phenotypic readout Annals of neurology High 23424178
2013 Budding yeast kinetochores (via the Ctf19 complex) recruit DDK (Cdc7-Dbf4) to pericentromeric regions in telophase; DDK at kinetochores promotes early firing of pericentromeric replication origins via Sld3-Sld7 recruitment, and independently recruits the Scc2-Scc4 cohesin loader to centromeres in G1, enhancing pericentromeric cohesion. ChIP-seq, live-cell fluorescence microscopy, genetic epistasis, immunoprecipitation Molecular cell High 23746350
2013 ATR-Chk1 signaling stabilizes the Cdc7-ASK/Dbf4 complex under replication stress by inactivating APC/C(Cdh1) through Chk1-mediated Cdh1 degradation; ASK motif C interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for RAD18 chromatin binding and loading of translesion DNA polymerase η. Co-immunoprecipitation, proteasome inhibitor experiments, chromatin fractionation, siRNA knockdown, RAD18 foci assay Genes & development High 24240236
2013 Dbf4 interacts most strongly with Mcm2 (via an N-terminal Mcm2 docking domain), while Cdc7 associates with Mcm4 and Mcm5; combining loss of the Mcm2-Dbf4 and Mcm4-Cdc7 docking interactions is synthetically lethal, establishing overlapping DDK-MCM docking interactions as essential for replication. Two-hybrid analysis, co-immunoprecipitation, synthetic lethality genetics The Journal of biological chemistry High 23549044
2014 Rif1 in budding yeast directs PP1 phosphatase to dephosphorylate MCM4 (reversing DDK-mediated phosphorylation); Rif1 PP1-interaction motifs are critical for replication repression; Rif1 itself is regulated by DDK phosphorylation near its PP1-binding motifs, creating a feedback loop. Co-immunoprecipitation (Rif1-PP1), phosphorylation assay, genetic analysis in cdc7-1 mutants, deletion mutant phenotyping Genes & development High 24532715
2016 Claspin recruits Cdc7 kinase to replication origins via an acidic patch (AP) near the C terminus; Cdc7-AP interaction is required for MCM phosphorylation; AP also mediates Cdc7-dependent intramolecular conformational change in Claspin that unmasks its DNA-binding domain and PIP motif. Conditional Claspin knockout MEF cells, mutant Claspin rescue, co-immunoprecipitation, MCM phosphorylation assay Nature communications High 27401717
2017 ATR inhibitor-induced unscheduled origin firing requires Cdc7 kinase activity; Cdc7 phosphorylates GINS subunits, inducing GINS-And-1 association that mediates the origin firing. Proteomic phosphorylation analysis, co-immunoprecipitation, CDC7 inhibitor experiments Nature communications Medium 29123096
2018 ADP generated from CDC7-mediated MCM phosphorylation binds an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity (product feedback inhibition); nuclear PGK1, phosphorylated at S256 by CK2α (activated by EGFR/ERK signaling), binds CDC7 and converts ADP to ATP, abrogating ADP-dependent feedback inhibition and promoting DNA helicase recruitment. In vitro kinase assay, co-immunoprecipitation, ADP-binding analysis, CK2α phosphorylation assay, chromatin fractionation Molecular cell High 30392930
2019 Cdc7 phosphorylates the Chk1-binding domain (CKBD) of Claspin in human cancer cells to facilitate Claspin-Chk1 interaction and activate the ATR-Chk1 checkpoint; in non-cancer cells, CK1γ1 predominantly phosphorylates CKBD instead of Cdc7, providing mechanistic basis for cancer cell-selective killing by Cdc7 inhibition. Conditional Cdc7 knockout, siRNA double-depletion, co-immunoprecipitation, in vitro kinase assay eLife High 31889509
2020 CDC7 localizes at replication forks and promotes MRE11-dependent slowing of fork progression upon mild topoisomerase inhibition; both CDC7 and MRE11 are retained on stalled forks for processing and restart; MRE11 phosphorylation and localization at replication factories require CDC7 activity. CDC7 activity at reversed forks is required for pathological MRE11-dependent fork degradation in BRCA2-deficient cells. Chemical-genetic CDC7 inhibition, DNA fiber analysis, electron microscopy of replication intermediates, MRE11 localization by immunofluorescence EMBO reports High 32496651
2022 Cryo-EM structures of yeast DDK bound to the MCM double hexamer show that Dbf4 (via its HBRCT domain) anchors to Mcm2, enabling DDK to bridge the hexamer interface and phosphorylate Mcm4 on the opposite hexamer; Dbf4 displaces the Mcm4 NSD from its binding site, facilitating Cdc7 targeting; a Dbf4 inhibitory loop occupies Cdc7's active center and is disengaged upon kinase conformational flexibility. Cryo-electron microscopy, biochemical phosphorylation assay, domain mutagenesis Nature communications High 35296675 35614055
2022 CDC7 is dispensable for S-phase entry in many mammalian cell types when CDK1 is active; CDC7 and CDK1 perform functionally redundant roles at the G1/S transition (at least one must be present); CDK1 is physiologically active during G1/S in cycling cells and cells exiting quiescence. Chemical genetic acute protein degradation (degron tagging of CDC7), CDK1 inhibitor co-treatment, cell-cycle analysis in cultured cells and in vivo in mice Nature High 35508654

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Molecular cell 295 12535533
2010 How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes & development 275 20551170
1997 Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis. Genes & development 259 9407029
2010 The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature 248 20054399
1998 The Cdc7 protein kinase is required for origin firing during S phase. Genes & development 244 9472017
1993 Cell cycle regulation of the yeast Cdc7 protein kinase by association with the Dbf4 protein. Molecular and cellular biology 217 8474449
2014 Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes & development 183 24532715
1999 Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. The EMBO journal 181 10523313
2008 A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nature chemical biology 180 18469809
1998 Cdc7 is required throughout the yeast S phase to activate replication origins. Genes & development 180 9472018
1994 Interaction of Dbf4, the Cdc7 protein kinase regulatory subunit, with yeast replication origins in vivo. Science (New York, N.Y.) 179 8066465
2006 Phosphorylation of MCM4 by Cdc7 kinase facilitates its interaction with Cdc45 on the chromatin. The Journal of biological chemistry 154 17046832
2010 Rec8 phosphorylation by casein kinase 1 and Cdc7-Dbf4 kinase regulates cohesin cleavage by separase during meiosis. Developmental cell 152 20230747
2008 Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell 151 19013276
2002 Cdc7 kinase complex: a key regulator in the initiation of DNA replication. Journal of cellular physiology 147 11857444
1994 The cdc7 protein kinase is a dosage dependent regulator of septum formation in fission yeast. The EMBO journal 143 8039497
2010 Mec1 is one of multiple kinases that prime the Mcm2-7 helicase for phosphorylation by Cdc7. Molecular cell 137 21070963
2000 Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks. The Journal of biological chemistry 136 10846177
1995 hsk1+, a Schizosaccharomyces pombe gene related to Saccharomyces cerevisiae CDC7, is required for chromosomal replication. The EMBO journal 134 7621824
2000 Xenopus cdc7 function is dependent on licensing but not on XORC, XCdc6, or CDK activity and is required for XCdc45 loading. Genes & development 133 10859170
2000 Evidence for sequential action of cdc7 and cdk2 protein kinases during initiation of DNA replication in Xenopus egg extracts. The Journal of biological chemistry 130 11005825
1997 Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7. The EMBO journal 123 9250678
2004 Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. Cancer research 122 15466207
2013 Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment. Molecular cell 119 23746350
2008 Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes & development 113 18245450
2008 Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. Neoplasia (New York, N.Y.) 111 18714392
2008 Cdc7-dependent phosphorylation of Mer2 facilitates initiation of yeast meiotic recombination. Genes & development 110 18245451
1999 A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells. Molecular and cellular biology 110 10373557
1999 A role for the Cdc7 kinase regulatory subunit Dbf4p in the formation of initiation-competent origins of replication. Genes & development 110 10465792
1986 Molecular characterization of cell cycle gene CDC7 from Saccharomyces cerevisiae. Molecular and cellular biology 108 3537706
2013 CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Annals of neurology 107 23424178
2000 Hierarchy of S-phase-promoting factors: yeast Dbf4-Cdc7 kinase requires prior S-phase cyclin-dependent kinase activation. Molecular and cellular biology 100 10805723
2008 Cdc7-Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts. Genes & development 99 18628396
2020 Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair. Nature communications 91 32355159
2007 Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene 78 18084324
2012 Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorganic & medicinal chemistry letters 77 22560567
2006 CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein. Proceedings of the National Academy of Sciences of the United States of America 77 16864800
1990 DNA metabolism gene CDC7 from yeast encodes a serine (threonine) protein kinase. Proceedings of the National Academy of Sciences of the United States of America 76 2166954
2017 ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1. Nature communications 73 29123096
2006 Cdc7 is an active kinase in human cancer cells undergoing replication stress. The Journal of biological chemistry 73 17062569
2022 CDC7-independent G1/S transition revealed by targeted protein degradation. Nature 71 35508654
2002 Inactivation of Cdc7 kinase in mouse ES cells results in S-phase arrest and p53-dependent cell death. The EMBO journal 71 11980714
2002 Drf1, a novel regulatory subunit for human Cdc7 kinase. The EMBO journal 69 12065429
1988 Differential regulation of the yeast CDC7 gene during mitosis and meiosis. Molecular and cellular biology 69 3275871
2000 The Cdc7/Dbf4 protein kinase: target of the S phase checkpoint? EMBO reports 68 11269496
1993 Regulation of Saccharomyces cerevisiae CDC7 function during the cell cycle. Molecular biology of the cell 68 8382976
2013 ATR-Chk1-APC/CCdh1-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress. Genes & development 67 24240236
2008 Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships. Journal of medicinal chemistry 67 18201066
2010 Cdc7 kinase - a new target for drug development. European journal of cancer (Oxford, England : 1990) 66 19815406
2008 The Hsk1(Cdc7) replication kinase regulates origin efficiency. Molecular biology of the cell 63 18799612
2018 Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication. Molecular cell 61 30392930
2012 Crystal structure of human CDC7 kinase in complex with its activator DBF4. Nature structural & molecular biology 61 23064647
2009 Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 61 19318489
2006 The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen. EMBO reports 58 16826239
2009 Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. The Journal of biological chemistry 56 19864417
2007 Cdc7-Dbf4 and the human S checkpoint response to UVC. The Journal of biological chemistry 56 17276990
2005 Cdc7-Drf1 is a developmentally regulated protein kinase required for the initiation of vertebrate DNA replication. Genes & development 56 16204181
2009 Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. The Journal of biological chemistry 55 19692334
1998 A human homolog of the yeast CDC7 gene is overexpressed in some tumors and transformed cell lines. Gene 55 9573348
1991 The CDC7 protein of Saccharomyces cerevisiae is a phosphoprotein that contains protein kinase activity. Proceedings of the National Academy of Sciences of the United States of America 54 2023904
2019 A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy. Breast cancer research : BCR 53 31262335
2009 First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. Journal of medicinal chemistry 53 19115845
2019 Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor. Science advances 52 31131319
2006 Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint. Molecular and cellular biology 52 16479016
2003 Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development. Mutation research 52 14643427
2008 The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control. Molecular cell 51 19111665
2001 Bipartite binding of a kinase activator activates Cdc7-related kinase essential for S phase. The Journal of biological chemistry 51 11402029
1994 Cdc7 protein kinase for DNA metabolism comes of age. Molecular microbiology 48 8022258
2010 Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers. The American journal of pathology 47 20724597
2002 Novel fission yeast Cdc7-Dbf4-like kinase complex required for the initiation and progression of meiotic second division. Molecular and cellular biology 46 11739743
2008 ATR-dependent activation of p38 MAP kinase is responsible for apoptotic cell death in cells depleted of Cdc7. The Journal of biological chemistry 45 18625709
2010 Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. Journal of medicinal chemistry 43 20873740
1992 Molecular genetic studies of the Cdc7 protein kinase and induced mutagenesis in yeast. Genetics 43 1398063
2013 Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents. Cancer letters 42 23684929
2003 Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex. Genes to cells : devoted to molecular & cellular mechanisms 42 12694534
2017 p53 gain-of-function mutations increase Cdc7-dependent replication initiation. EMBO reports 41 28887320
2007 Structural changes in Mcm5 protein bypass Cdc7-Dbf4 function and reduce replication origin efficiency in Saccharomyces cerevisiae. Molecular and cellular biology 41 17724082
1998 Growth regulation of the expression of mouse cDNA and gene encoding a serine/threonine kinase related to Saccharomyces cerevisiae CDC7 essential for G1/S transition. Structure, chromosomal localization, and expression of mouse gene for s. cerevisiae Cdc7-related kinase. The Journal of biological chemistry 41 9722556
2016 Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells. Nature communications 40 27401717
2014 Regulation and roles of Cdc7 kinase under replication stress. Cell cycle (Georgetown, Tex.) 39 24841992
2011 Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells. Molecular cancer therapeutics 39 21768328
2003 Cdc7 kinases (DDKs) and checkpoint responses: lessons from two yeasts. Mutation research 38 14643426
1999 DNA replication in vertebrates requires a homolog of the Cdc7 protein kinase. Proceedings of the National Academy of Sciences of the United States of America 38 10077591
2020 ATR Restrains DNA Synthesis and Mitotic Catastrophe in Response to CDC7 Inhibition. Cell reports 35 32877678
2021 Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer. Genome medicine 34 34663432
2019 Cdc7 activates replication checkpoint by phosphorylating the Chk1-binding domain of Claspin in human cells. eLife 33 31889509
2013 Dbf4 and Cdc7 proteins promote DNA replication through interactions with distinct Mcm2-7 protein subunits. The Journal of biological chemistry 33 23549044
2002 A 63-base pair DNA segment containing an Sp1 site but not a canonical E2F site can confer growth-dependent and E2F-mediated transcriptional stimulation of the human ASK gene encoding the regulatory subunit for human Cdc7-related kinase. The Journal of biological chemistry 33 12015319
2013 MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung cancer cells. Oncogenesis 32 23877787
2008 Cdc7-Dbf4 regulates NDT80 transcription as well as reductional segregation during budding yeast meiosis. Molecular biology of the cell 32 18768747
2022 The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer. Nature communications 31 35614055
2013 Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint. Cell cycle (Georgetown, Tex.) 31 23598722
1999 CDC7 kinase complex as a molecular switch for DNA replication. Frontiers in bioscience : a journal and virtual library 30 10577390
1991 CDC7 protein kinase activity is required for mitosis and meiosis in Saccharomyces cerevisiae. Molecular & general genetics : MGG 30 1865880
2022 Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase. Nature communications 29 35296675
2014 The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PloS one 29 25412417
2020 CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage. EMBO reports 28 32496651
2017 DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors. ACS chemical biology 28 28560864
2018 Inhibition of checkpoint kinase 1 following gemcitabine-mediated S phase arrest results in CDC7- and CDK2-dependent replication catastrophe. The Journal of biological chemistry 27 30573684
2009 Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug design, development and therapy 27 19920912

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