Affinage

CDC7

Cell division cycle 7-related protein kinase · UniProt O00311

Length
574 aa
Mass
63.9 kDa
Annotated
2026-04-28
100 papers in source corpus 51 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC7 is a conserved serine/threonine kinase that, together with its regulatory subunit DBF4 (ASK), forms the DDK complex essential for the initiation and timing of DNA replication, meiotic recombination, replication checkpoint signaling, and replication fork processing. DBF4 recruits CDC7 to chromatin-bound MCM2-7 double hexamers at licensed origins, where cryo-EM structures show DBF4 anchors to MCM2 and displaces the inhibitory N-terminal domain of MCM4, enabling CDC7 to phosphorylate MCM4, MCM2, and MCM6 and thereby promote CDC45 loading and helicase activation (PMID:35296675, PMID:20054399, PMID:17046832). CDC7 functions in parallel with CDK1 at the G1/S transition—either kinase alone suffices for S-phase entry—and is further regulated by CDK-mediated phosphorylation at Thr-376, by ADP-mediated allosteric autoinhibition relieved by nuclear PGK1, and by Rif1-PP1 opposition of MCM phosphorylation (PMID:35508654, PMID:10846177, PMID:30392930, PMID:24532715). Beyond origin firing, CDC7 phosphorylates Claspin to activate ATR-Chk1 checkpoint signaling, mediates MRE11-dependent replication fork processing independently of origin firing, promotes RAD18-dependent translesion synthesis, phosphorylates Mer2 to initiate meiotic double-strand breaks, and phosphorylates TDP-43 at pathological Ser409/410 sites linked to neurodegeneration (PMID:18084324, PMID:32496651, PMID:24240236, PMID:19013276, PMID:23424178).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1986 High

    Establishing that CDC7 encodes a serine/threonine kinase required for mitotic DNA synthesis answered the fundamental question of what biochemical activity this essential cell-cycle gene provides.

    Evidence Sequence analysis revealing kinase-domain homology and genetic complementation of cdc7 temperature-sensitive mutants in S. cerevisiae

    PMID:3537706

    Open questions at the time
    • Substrates unknown
    • Regulatory mechanism unknown
    • Conservation in metazoans not yet demonstrated
  2. 1992 High

    Identification of DBF4 as a genetic interactor and functional partner of CDC7 established that CDC7 operates as a two-subunit kinase complex, analogous to cyclin-CDK pairs.

    Evidence Dosage-dependent and allele-specific suppression between DBF4 and CDC7 in yeast genetics

    PMID:1592236

    Open questions at the time
    • Physical interaction not yet demonstrated biochemically
    • Nature of activation mechanism unclear
  3. 1997 High

    Demonstration that Cdc7-Dbf4 directly phosphorylates MCM2, MCM3, MCM4, and MCM6 identified the MCM helicase complex as the critical substrate linking CDC7 to replication initiation.

    Evidence Genetic suppressor screen, co-immunoprecipitation, and in vitro kinase assays in yeast and human systems

    PMID:9250678 PMID:9407029

    Open questions at the time
    • Specific phosphorylation sites on MCM subunits unknown
    • Functional consequence of MCM phosphorylation not yet determined
  4. 1999 High

    Reconstitution of the human CDC7-ASK complex and demonstration that DBF4 targets CDC7 to chromatin-bound pre-replication complexes resolved how the kinase reaches its substrates at replication origins.

    Evidence Baculovirus co-expression, antibody microinjection blocking replication in HeLa cells, chromatin fractionation showing ORC-dependent DBF4 puncta in yeast

    PMID:10373557 PMID:10465792 PMID:10523313

    Open questions at the time
    • Structural basis of DBF4-origin interaction unresolved
    • Whether CDC7 has origin-independent roles unknown
  5. 2000 High

    Placing CDC7 upstream of CDC45 chromatin loading and showing CDK phosphorylation at Thr-376 activates CDC7 defined the hierarchical position of CDC7 in the initiation cascade and its dependence on CDK priming.

    Evidence Xenopus egg extract immunodepletion epistasis and in vitro mutagenesis of T376A abolishing kinase activity

    PMID:10846177 PMID:10859170

    Open questions at the time
    • How CDK and CDC7 coordinate temporally at individual origins unresolved
    • Whether CDC7 and CDK are strictly ordered or partially redundant
  6. 2006 High

    Mapping CDC7 phosphorylation sites on MCM2 (S5, S53) and MCM4 N-terminal S/T-P residues, and showing phosphomimetic MCM2 activates MCM ATPase and rescues replication, established that CDC7 phosphorylation directly activates the replicative helicase.

    Evidence Alanine-scanning mutagenesis, phosphomimetic rescue of MCM2 siRNA knockdown in HeLa cells, phospho-specific antibodies in Cdc7 knockout ES cells

    PMID:16864800 PMID:16899510 PMID:17046832

    Open questions at the time
    • Structural mechanism of how phosphorylation relieves MCM4-NSD inhibition unknown
    • Relative contributions of individual MCM subunit phosphorylation not separated
  7. 2007 High

    Discovery that CDC7 phosphorylates Claspin and is required for ATR-Chk1 activation established a checkpoint function for CDC7 beyond origin firing.

    Evidence Conditional Cdc7 knockout mouse ES cells and siRNA depletion showing loss of Chk1 phosphorylation with intact ATR/Rad17 chromatin localization

    PMID:18084324

    Open questions at the time
    • Whether checkpoint function is separable from replication-initiation function in vivo
    • Direct phosphorylation sites on Claspin not yet mapped
  8. 2008 High

    Demonstration that DDK phosphorylates Mer2 (primed by CDK-S) to promote meiotic DSB formation and phosphorylates monopolin Lrs4 for kinetochore mono-orientation revealed CDC7 as a master coordinator of meiotic chromosome events.

    Evidence Chemical-genetic CDC7 inhibition with phosphomimetic bypass of DSB requirement, ChIP and kinetochore assays in yeast meiosis

    PMID:18245450 PMID:19013276

    Open questions at the time
    • Whether CDC7 meiotic substrates are conserved in mammals
    • Full complement of meiotic CDC7 substrates unknown
  9. 2010 High

    Genetic demonstration that DDK's sole essential function is to relieve the inhibitory Mcm4-NSD simplified the model: DDK activates replication by removing an intrinsic block within the MCM complex.

    Evidence Mcm4-ΔNSD combined with CDK bypass mutations enabling DNA replication in G1 without DDK in S. cerevisiae

    PMID:20054399

    Open questions at the time
    • Whether NSD-relief model applies to metazoan CDC7
    • Structural basis of NSD autoinhibition unresolved
  10. 2012 High

    The crystal structure of human CDC7-DBF4 revealed how DBF4 wraps around CDC7, stabilizes the αC helix for activation via motif C, and tethers via motif M, providing the first structural framework for DDK function and inhibitor design.

    Evidence X-ray crystallography of CDC7-DBF4 in active and inhibitor-bound forms

    PMID:23064647

    Open questions at the time
    • Structure of DDK bound to MCM substrate not yet available
    • Mechanism of substrate recognition not resolved at atomic level
  11. 2013 High

    Identification of TDP-43 as a CDC7 substrate at pathological Ser409/410, with inhibitor-mediated neuroprotection, expanded CDC7 function to neurodegeneration-relevant phosphorylation beyond DNA replication.

    Evidence RNAi kinase screen in C. elegans, in vitro kinase assay, and PHA767491-mediated rescue of TDP-43 neurodegeneration in transgenic animals

    PMID:23424178

    Open questions at the time
    • Whether CDC7 is the physiologically dominant TDP-43 kinase in human neurons
    • Therapeutic window of CDC7 inhibition for neurodegeneration not established
  12. 2014 High

    Discovery that Rif1-PP1 opposes DDK by dephosphorylating MCM4, and that DDK phosphorylates Rif1 near its PP1-binding motifs, revealed a reciprocal regulatory circuit controlling replication timing genome-wide.

    Evidence Genetic epistasis of cdc7-1 with rif1Δ, phospho-specific Mcm4 antibodies, PP1 co-immunoprecipitation in yeast

    PMID:24532715

    Open questions at the time
    • Structural basis of Rif1-PP1-DDK interplay unknown
    • How this circuit achieves origin-specific timing regulation
  13. 2018 High

    Identification of ADP-mediated allosteric autoinhibition of CDC7 and its relief by nuclear PGK1 linked growth-factor signaling (EGFR-ERK-CK2α-PGK1) to DNA replication control through CDC7 metabolic regulation.

    Evidence In vitro ADP binding and kinase assays with mutagenesis, co-immunoprecipitation of PGK1-CDC7, helicase recruitment assays

    PMID:30392930

    Open questions at the time
    • Whether ADP feedback operates on other DDK substrates beyond MCM
    • In vivo quantitation of nuclear ADP/ATP ratio effects on CDC7
  14. 2020 High

    Demonstration that CDC7 is dispensable when CDK1 is active at G1/S—and vice versa—fundamentally revised the two-kinase model from sequential to functionally redundant, explaining why CDC7 loss is tolerated in many cell types.

    Evidence Acute chemical-genetic CDC7 shutdown in mouse tissues and cultured cells combined with CDK1 inhibition

    PMID:35508654

    Open questions at the time
    • Whether specific cancer contexts restore CDC7 essentiality
    • Molecular basis of CDK1 compensatory MCM phosphorylation unclear
  15. 2020 High

    CDC7 was shown to regulate MRE11-dependent fork processing at stalled forks independently of origin firing, establishing a replication-fork-proximal function distinct from its canonical initiation role.

    Evidence Chemical-genetic CDC7 inhibition, DNA fiber assays, MRE11 localization at replication factories, fork degradation assays in BRCA2-deficient cells

    PMID:32496651

    Open questions at the time
    • Direct CDC7 phosphorylation sites on MRE11 not identified
    • Whether fork-processing function is relevant in CDC7 inhibitor therapeutic contexts
  16. 2022 High

    Cryo-EM structures of DDK bound to the MCM double hexamer revealed that DBF4-HBRCT anchors to MCM2 and Cdc7 rotates to sequentially phosphorylate MCM4-NSD, MCM2, and MCM6 across the hexamer interface, providing the structural mechanism for substrate engagement and NSD displacement.

    Evidence Cryo-EM of DDK-MCM double hexamer complexes in multiple conformational states, two independent studies

    PMID:35296675 PMID:35614055

    Open questions at the time
    • Whether metazoan DDK-MCM structure differs
    • Mechanism by which CDK1 can substitute for DDK at the structural level unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: what determines cell-type-specific CDC7 essentiality versus CDK1 redundancy; the structural basis of CDC7 action at replication forks (fork processing, Claspin phosphorylation) as opposed to origins; and whether CDC7 inhibitors can be therapeutically exploited in specific cancer or neurodegenerative contexts.
  • No structure of CDC7 at a replication fork
  • Therapeutic selectivity window for CDC7 inhibition in cancer versus normal cells undefined
  • Full catalog of non-MCM CDC7 substrates in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016740 transferase activity 6
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 3
Pathway
R-HSA-69306 DNA Replication 7 R-HSA-1640170 Cell Cycle 4 R-HSA-73894 DNA Repair 4 R-HSA-1474165 Reproduction 2
Partners
CLSPNDBF4MCM2MCM4MCM6MRE11PGK1PSIP1
Complex memberships
DDK (CDC7-DBF4/ASK)DDK (CDC7-DRF1)

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 CDC7 encodes a protein kinase (serine/threonine kinase) required for initiation of mitotic DNA synthesis, meiotic recombination, and error-prone DNA repair in S. cerevisiae, as determined by sequence analysis revealing kinase domain homology and genetic complementation of cdc7 temperature-sensitive mutants. Nucleotide sequencing, genetic complementation, marker rescue Molecular and cellular biology High 3537706
1988 CDC7-dependent protein kinase activity co-purifies with the yeast DNA replication complex and phosphorylates a 48-kDa polypeptide on serine residues, linking CDC7 kinase activity directly to the replication machinery. Biochemical purification of replicative complex, in vitro kinase assay, heat-sensitivity in cdc7 mutant extracts Proceedings of the National Academy of Sciences of the United States of America Medium 3281161
1992 DBF4 (regulatory subunit) suppresses cdc7 temperature-sensitive mutations in a dosage-dependent and allele-specific manner, and CDC7 overexpression suppresses dbf4 mutations, establishing that CDC7 and DBF4 gene products interact directly or indirectly to permit initiation of chromosome replication. Genetic suppression, multicopy plasmid complementation, epistasis analysis Genetics High 1592236
1993 Cdc7 kinase activity oscillates during the cell cycle (peaking at G1/S), is dependent on phosphorylation state (phosphatase treatment abolishes activity), and Cdc28 kinase contributes to Cdc7 phosphorylation and activation at a consensus Cdc28 site. Immunoprecipitation kinase assay, in vitro phosphatase treatment, phosphopeptide mapping, cell cycle synchronization Molecular biology of the cell High 8382976
1994 Dbf4 protein interacts with Cdc7 kinase and with yeast replication origins in vivo (demonstrated by two-hybrid and one-hybrid assays), suggesting Dbf4 recruits Cdc7 kinase to initiation complexes at origins. Two-hybrid and one-hybrid assays Science (New York, N.Y.) High 8066465
1995 Hsk1, the S. pombe ortholog of Cdc7, is an essential serine/threonine kinase required for chromosomal DNA replication (not mitosis per se), establishing conservation of the CDC7 replication-initiation function in fission yeast. Gene disruption (null allele), DNA content analysis of germinating spores, sequence analysis The EMBO journal High 7621824
1997 Cdc7-Dbf4 physically interacts with Mcm2, phosphorylates Mcm2 and three other MCM2-7 family members (Mcm3, Mcm4, Mcm6) in vitro, and blocking Cdc7-Dbf4 kinase activity at G1/S blocks Mcm2 phosphorylation; DBF4 was identified as a suppressor of mcm2-1, establishing MCM2-7 as critical substrates. Genetic suppressor screen, co-immunoprecipitation, in vitro kinase assay, cell cycle synchronization Genes & development High 9407029
1997 Human CDC7 (huCdc7) phosphorylates MCM2 and MCM3 proteins in vitro, demonstrating conservation of MCM substrate specificity in mammalian CDC7. In vitro kinase assay with COS7-expressed huCdc7 The EMBO journal Medium 9250678
1998 Cdc7 is required not only for S-phase entry but also during S phase for the timely firing of late-firing replication origins, demonstrating a direct role at individual origins throughout S phase. Partial loss-of-function analysis, hydroxyurea block-release, 2D gel analysis of origin firing Genes & development High 9472017
1998 Purified fission yeast Hsk1 (Cdc7 ortholog) forms a heterodimer with Dfp1 (Dbf4 ortholog); Dfp1 association stimulates phosphorylation of exogenous substrates but not autokinase activity; purified Hsk1 phosphorylates the Cdc19 (Mcm2) subunit of the MCM complex; point mutations in conserved kinase regions abolish activity in vitro and in vivo. Protein purification (~30,000-fold), in vitro kinase assay, site-directed mutagenesis, dominant-negative analysis The Journal of biological chemistry High 9705352
1999 Human Dbf4 homolog (HsDbf4/ASK) binds HsCdc7 and activates its kinase activity; the purified HsCdc7-HsDbf4 complex selectively phosphorylates MCM2 in vitro at sites matching in vivo phosphopeptides; microinjection of anti-HsCdc7 antibodies blocks initiation of DNA replication in HeLa cells. Co-immunoprecipitation, baculovirus co-expression, in vitro kinase assay, 2D phosphopeptide mapping, antibody microinjection The EMBO journal High 10523313
1999 ASK (activator of S-phase kinase, human Dbf4 homolog) is identified as the major activator of huCdc7 by forming an active kinase complex that phosphorylates MCM2; ASK immunodepletion eliminates huCdc7-dependent kinase activity; ASK levels oscillate with cell cycle (peaking in S phase); microinjection of ASK antibodies inhibits DNA replication, establishing ASK as essential regulatory subunit. Two-hybrid screen, co-immunoprecipitation, immunodepletion kinase assay, cell cycle synchronization, antibody microinjection Molecular and cellular biology High 10373557
1999 The Dbf4/Cdc7 kinase complex must be provided by the template nuclei (chromatin-associated) for initiation; Dbf4 accumulates on chromatin in late G1 in a punctate ORC-dependent pattern prior to Clb/Cdc28 activation, establishing that Dbf4 targets Cdc7 to the prereplication complex (pre-RC) in a pathway parallel to but independent of Cdc6. Reconstituted yeast DNA replication assay, chromatin fractionation, immunofluorescence localization Genes & development High 10465792
1999 Dfp1 (fission yeast Dbf4) is necessary and sufficient to activate Hsk1 phosphorylation of exogenous substrates; Dfp1 is essential for viability and depletion delays S-phase onset; Dfp1 becomes hyperphosphorylated during S-phase arrest by the checkpoint kinase Cds1. Reconstitution with purified proteins, genetic depletion, cell cycle analysis, phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 10411894
2000 Xenopus Cdc7 (XCdc7) binds chromatin after origin licensing (requires MCM loading) but independently of ORC, Cdc6, or CDK activity; XCdc7 is required for subsequent CDK-dependent loading of XCdc45 onto chromatin, placing Cdc7 upstream of Cdc45 recruitment in the initiation cascade. Xenopus egg extract cell-free replication system, immunodepletion, chromatin fractionation, biochemical epistasis Genes & development High 10859170
2000 Human CDC7 (huCdc7) is phosphorylated by CDKs (Cdk2-CyclinE, Cdk2-CyclinA, Cdc2-CyclinB) at Thr-376 (analogous to T-loop of CDKs), and T376A mutation dramatically reduces kinase activity, revealing activation of CDC7 by CDK-mediated phosphorylation; CDK prior phosphorylation of MCM2-4-6-7 complex facilitates subsequent huCdc7 phosphorylation of MCM2. In vitro kinase assay, site-directed mutagenesis (T376A), baculovirus expression, purified kinase reconstitution The Journal of biological chemistry High 10846177
2000 DDK (Dbf4-Cdc7) activity is cell-cycle regulated primarily through Dbf4 levels, which are destabilized by APC/C in G1; joint Cdc7 and Dbf4 overexpression is lethal; DDK can perform its replication function only after S-CDK (Clb5-Cdk1) activation, establishing a hierarchy; Cdc45 is phosphorylated by DDK in vitro, identifying it as a candidate DDK substrate downstream of CDK. Cell cycle synchronization, kinase assays, genetic epistasis, in vitro phosphorylation Molecular and cellular biology High 10805723
2001 Dbf4 motifs M (proline-rich) and C (C2H2 zinc finger) both bind and partially activate Hsk1 (Cdc7 ortholog); bipartite binding through both motifs is required for full kinase activation and mitotic function; Dbf4 motif N (BRCA-CT-like) is dispensable for kinase activation but required for checkpoint responses and origin interaction. Deletion and point mutagenesis of Dfp1/Him1, in vitro kinase reconstitution, one-hybrid assay, cell viability assays The Journal of biological chemistry High 11402029
2002 Drf1, a second human regulatory subunit related to Dbf4, binds CDC7 and activates its kinase activity, demonstrating that human CDC7 can be activated by alternative regulatory subunits analogous to cyclin-CDK pairs. Co-immunoprecipitation, kinase activity assay, cell cycle expression analysis The EMBO journal High 12065429
2003 Cdc23 (Mcm10 homolog) is required for efficient phosphorylation of the Mcm2 and Mcm4 subunits within the six-subunit MCM complex by Dfp1-Hsk1 (Cdc7-Dbf4); Cdc23 bridges the interaction by binding Mcm467 and Dfp1 simultaneously, serving as a scaffold to recruit DDK to the MCM complex. In vitro kinase assay with purified proteins, co-immunoprecipitation, deletion analysis Proceedings of the National Academy of Sciences of the United States of America High 12604790
2003 Hsk1 (S. pombe Cdc7 ortholog) interacts with and phosphorylates the heterochromatin protein Swi6 (HP1 equivalent), and Hsk1-Dfp1 function downstream of Swi6 localization to promote centromere cohesion independently of replication initiation function. Co-immunoprecipitation, in vitro kinase assay, genetic epistasis with heterochromatin mutants, cohesion assays Nature cell biology High 14625560
2003 Human Cdc7-ASK (huCdc7) is imported into the nucleus via importin-beta binding to the Kinase Insert II domain of Cdc7; importin-alpha competes for the same binding site but with ~10-fold lower affinity; Lys306 and Lys309 within Kinase Insert II are critical for nuclear localization. Co-immunoprecipitation, importin immunodepletion/add-back, antibody transduction into live cells, site-directed mutagenesis The Journal of biological chemistry High 16492669
2003 Human Cdc7 protein is imported into nuclei at early G1 and binds chromatin, while ASK accumulates in nuclei at telophase but binds chromatin maximally at late G1, showing that nuclear localization and chromatin binding of CDC7 and ASK are independently regulated; overexpression of both huCdc7 and ASK elevates endogenous MCM2 phosphorylation. GFP fusion localization, fractionation, cell cycle synchronization, immunoblotting Genes to cells : devoted to molecular & cellular mechanisms Medium 12694534
2006 Cdc7 kinase phosphorylates serine residues adjacent to acidic amino acids on human MCM2; the two major sites are S5 and S53; an adjacent CDK-phosphorylated residue (pS27) can create a new Cdc7 site on S26, providing a biochemical mechanism for sequential CDK→CDC7 phosphorylation. In vitro kinase assay with truncated proteins and peptides, alanine-scanning mutagenesis, synthetic phosphopeptides Proceedings of the National Academy of Sciences of the United States of America High 16864800
2006 Cdc7 phosphorylates Mcm4 N-terminal (S/T)(S/T)P residues on chromatin in an S-phase-specific manner; phospho-Mcm4 stimulates association of Cdc45 with chromatin; N-terminal deletion of Mcm4 combined with alanine substitution of Mcm2 and Mcm6 N-terminal Cdc7 target sequences causes synthetic lethality. Phospho-specific antibodies, siRNA knockdown of Cdc7, Cdc7 knockout mouse ES cells, chromatin fractionation, Cdc45 co-IP, mutagenesis The Journal of biological chemistry High 17046832
2006 Phosphomimetic MCM2E (Cdc7/Dbf4 phosphorylation sites) in the MCM2-7 complex displays higher ATPase activity compared to non-phosphorylatable MCM2A-7; MCM2A cannot rescue DNA replication inhibition caused by MCM2 siRNA knockdown in HeLa cells, demonstrating Cdc7 phosphorylation of MCM2 is essential for replication initiation. Phosphomimetic mutagenesis, baculovirus expression of MCM2-7 complex, ATPase assay, siRNA rescue experiment, immunoblotting Molecular biology of the cell High 16899510
2006 Cdc7-Dbf4 kinase directly interacts with and phosphorylates the p150 subunit of chromatin assembly factor 1 (CAF1); this phosphorylation changes p150 oligomerization state and promotes its binding to PCNA, linking Cdc7 activity to coordinated chromatin assembly during replication. Co-immunoprecipitation (in vivo S-phase specific complex), in vitro kinase assay, oligomerization and PCNA-binding assays, Cdc7-depleted extract reconstitution EMBO reports High 16826239
2007 Cdc7 kinase interacts with and phosphorylates Claspin; Cdc7 deletion in mouse ES cells or siRNA depletion in human cancer cells abrogates HU- or UV-induced Chk1 activation while ATR and Rad17 relocate normally to chromatin; Cdc7-depleted cells show defects in Claspin chromatin association and phosphorylation, placing Cdc7 upstream of Claspin in the ATR-Chk1 checkpoint pathway. Co-immunoprecipitation, in vitro kinase assay, Cdc7 conditional knockout ES cells, siRNA, chromatin fractionation, Chk1 phosphorylation assay Oncogene High 18084324
2008 DDK (Cdc7-Dbf4) in yeast meiosis promotes double-strand break formation (first step of recombination) and recruits the monopolin complex to kinetochores through phosphorylation of monopolin subunit Lrs4, coordinating DNA replication initiation, recombination, and meiotic chromosome segregation. Chemical-genetic CDC7 inhibition, chromatin immunoprecipitation, kinetochore localization assays, meiotic DSB assays Cell High 19013276
2008 CDK-S (Cdc28-Clb5) phosphorylates Mer2 Ser30, priming Mer2 for subsequent phosphorylation by DDK (Cdc7-Dbf4) on Ser29; the dual phosphorylation creates a negatively charged patch required for meiotic DSB formation; phosphomimetic mutations at both sites bypass DDK and CDK-S requirements for DSB formation. Phosphomimetic and phosphonull mutagenesis, chemical-genetic CDK inhibition, meiotic DSB assays, in vitro kinase assay Genes & development High 18245450
2008 Cdc7-Dbf4 phosphorylates Rad53 in vitro, and Cdc7-Dbf4-deficient cells show hypophosphorylated Rad53 and impaired replication checkpoint responses under HU treatment, establishing Cdc7-Dbf4 as required for full Rad53 activation during replication stress. In vitro kinase assay with recombinant Cdc7-Dbf4, genetic deletion combined with mcm5-bob1 bypass, checkpoint readouts Gene Medium 18372119
2008 DDK (Cdc7-Dbf4) and CDK-S are activated independently, but DDK can perform its DNA replication function only after CDK-S activation; conversely, addition of purified DDK or Dbf4 overexpression attenuates ATR-Chk1 checkpoint signaling and overrides replication inhibition, establishing DDK as an upstream regulator (not a target) of the S-phase checkpoint. Xenopus egg extract reconstitution, immunodepletion, recombinant protein addition, HeLa cell overexpression, checkpoint readouts Molecular cell High 19111665
2009 Incorporation of Mcm2-7 into the prereplicative complex (pre-RC) increases DDK phosphorylation efficiency and changes its specificity; DDK associates with Mcm2-7 in a Dbf4-dependent manner; DDK association with and phosphorylation of origin-linked Mcm2-7 requires prior phosphorylation of the pre-RC. Cell-free reconstitution with purified pre-RC components, in vitro kinase assay, biochemical fractionation Genes & development High 19270162
2009 Dbf4 alone binds tightly to Mcm2 whereas Cdc7 alone binds weakly, indicating Dbf4 recruits Cdc7 to phosphorylate Mcm2; DDK phosphorylates Mcm2 at Ser-164 and Ser-170, and mcm2-S170A is lethal unless rescued by the DDK bypass mutation mcm5-bob1. Purified protein binding assays, in vitro kinase assay, phosphorylation site mapping, yeast genetics (lethality rescue) The Journal of biological chemistry High 19692334
2009 Cdc7 phosphorylation of Mcm2 promotes Mcm2 loading onto chromatin during cell-cycle re-entry from quiescence; a phosphomimetic MCM2 mutant bypasses the requirement for Cdc7 in MCM2 chromatin loading; cyclin E-Cdk2 promotes Cdc7 mRNA and protein accumulation, placing Cdc7 downstream of cyclin E-Cdk2 in pre-RC assembly. siRNA knockdown, phosphomimetic mutant rescue, chromatin fractionation, overexpression epistasis Molecular cell High 19647517
2009 LEDGF interacts with Cdc7-ASK (both subunits co-IP with endogenous LEDGF); LEDGF is phosphorylated by Cdc7-ASK at Ser-206 in vitro and in vivo; LEDGF stimulates CDC7-ASK kinase activity >10-fold (relieving autoinhibition imposed by C-terminus of ASK); interaction requires autophosphorylation of Cdc7-ASK and C-terminal 50 residues of ASK. Co-immunoprecipitation, in vitro kinase assay, truncation analysis, phosphosite identification The Journal of biological chemistry High 19864417
2010 The N-terminal serine/threonine-rich domain (NSD) of Mcm4 contains both inhibitory and facilitating activities for DNA replication; the sole essential function of DDK (Cdc7-Dbf4) is to relieve an inhibitory activity within the NSD; combining Mcm4-ΔNSD with CDK bypass mutations allows DNA synthesis in G1, demonstrating DDK and CDK act in parallel pathways to activate replication. Mcm4 deletion mutants, CDK bypass mutations, genetic epistasis, in vivo DNA replication assays in yeast Nature High 20054399
2010 Mec1 (ATR ortholog) is one of multiple kinases that prime Mcm4 and Mcm6 S/T-P or S/T-Q motifs for subsequent DDK (Cdc7-Dbf4) phosphorylation; Mrc1 facilitates Mec1 phosphorylation of chromatin-bound Mcm2-7 to activate replication; phosphomimetic mutations at DDK target sites bypass DDK function and priming site mutations. In vitro kinase assays, phosphomimetic mutants, genetic epistasis with MRC1/TOF1 deletions, S-phase progression analysis Molecular cell High 21070963
2010 Hsk1-Dfp1 (Cdc7-Dbf4 ortholog) acts as a diffusible, rate-limiting activator of replication origin efficiency; tethering Hsk1-Dfp1 near an origin increases its firing efficiency; FRAP demonstrates Hsk1-Dfp1 is freely diffusible in the nucleus. Hsk1-Dfp1 overexpression/depletion, origin tethering assay, FRAP, single-molecule DNA fiber analysis Molecular biology of the cell High 18799612
2010 Hsk1 (Cdc7 ortholog) phosphorylates the GATA factor Ams2, targeting it for SCF(Pof3)-dependent ubiquitylation and degradation; physical interaction of Hsk1 with Ams2 was demonstrated, and mild Ams2 overexpression causes centromere instability through aberrant canonical H3 incorporation, revealing a Cdc7 role in centromere maintenance through histone transcription control. Co-immunoprecipitation, in vitro kinase assay, genetic analysis of Ams2 overexpression, ChIP for histone incorporation Developmental cell High 20230746
2012 Crystal structure of human CDC7-DBF4 complex reveals DBF4 wraps around CDC7 burying ~6,000 Ų of hydrophobic interface; DBF4 motif C (effector domain) binds the CDC7 N-terminal lobe and stabilizes the canonical αC helix to activate the kinase; DBF4 motif M latches onto the C-terminal lobe as a tethering domain; structures captured in active (nucleotide-bound) and inhibited (small molecule-bound) forms. X-ray crystallography (crystal structures of CDC7-DBF4 with nucleotide and with inhibitors) Nature structural & molecular biology High 23064647
2013 CDC7 robustly phosphorylates TDP-43 at pathological residues Ser409/410 in C. elegans, in vitro, and in human cell culture; CDC7 inhibition with PHA767491 reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in transgenic animals. RNAi kinase screen in C. elegans, in vitro kinase assay, human cell culture phosphorylation, inhibitor treatment Annals of neurology High 23424178
2013 ATR-Chk1 signaling stabilizes the human Cdc7-ASK (Dbf4) complex by inhibiting APC/C(Cdh1)-mediated proteolysis during replication stress (Chk1 degrades Cdh1, stabilizing ASK); ASK (Dbf4) 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 polymerase η. Co-immunoprecipitation, ubiquitylation assays, chromatin fractionation, siRNA epistasis, RAD18 foci analysis Genes & development High 24240236
2013 Claspin is a direct in vitro substrate of Cdc7 kinase; Cdc7 inhibition delays HU-induced Chk1 phosphorylation without affecting Claspin chromatin association; Claspin interaction with Mcm2 is lost upon Cdc7 inhibition; mass spectrometry identified multiple Cdc7 phosphorylation sites on Claspin defining a Cdc7 consensus motif. In vitro kinase assay, mass spectrometry, small-molecule Cdc7 inhibitors, co-immunoprecipitation, Chk1 phosphorylation assays Cell cycle (Georgetown, Tex.) High 23598722
2014 Rif1 directs PP1 (Protein Phosphatase 1) to dephosphorylate the MCM complex, opposing DDK-mediated Mcm4 phosphorylation; PP1-interaction motifs in Rif1 are required for replication repression; deleting RIF1 compensates for limited DDK activity by allowing premature Mcm4 phosphorylation; Rif1 itself is phosphorylated by DDK near its PP1-binding motifs, creating a feedback regulatory mechanism. Genetic epistasis (cdc7-1 / rif1Δ), phospho-specific Mcm4 antibodies, PP1 co-immunoprecipitation, yeast genetics Genes & development High 24532715
2016 Claspin recruits Cdc7 kinase to facilitate MCM phosphorylation during normal DNA replication initiation; Claspin binds Cdc7 through its acidic patch (AP) near the C-terminus; Cdc7-mediated phosphorylation of Claspin reduces an intramolecular interaction that masks the DNA-binding domain and a PIP motif; Claspin knockout MEF cells show S-phase defects. Conditional Claspin knockout mice/MEFs, co-immunoprecipitation, Mcm phosphorylation assays, intramolecular interaction analysis, mutagenesis Nature communications High 27401717
2018 ADP generated from CDC7-mediated MCM phosphorylation binds allosterically to CDC7 and disrupts CDC7-ASK interaction, inhibiting kinase activity as negative feedback; nuclear PGK1 (phosphorylated at S256 by CK2α downstream of EGFR-ERK) interacts with CDC7 and converts ADP to ATP, relieving this negative feedback and promoting DNA replication. In vitro kinase assay, ADP binding assay, co-immunoprecipitation, site-directed mutagenesis, helicase recruitment assays Molecular cell High 30392930
2020 CDC7 is dispensable for S-phase entry in many cell types when acutely inactivated; CDK1 is active during G1/S and performs functionally redundant roles with CDC7 during G1/S transition; at least one of CDC7 or CDK1 must be present for S-phase entry, revising the model of CDC7 as an essential, non-redundant trigger. Chemical-genetic acute CDC7 shutdown (in culture and in vivo in mice), CDK1 activity assays, double-kinase inhibition, cell cycle analysis Nature High 35508654
2020 CDC7 activity is required for coordinating MRE11-dependent processes at replication forks independently of origin firing; CDC7 localizes at replication forks and mediates active fork slowing upon topoisomerase inhibition; CDC7 inhibition abolishes MRE11 phosphorylation and its localization at replication factories; CDC7 activity at reversed forks promotes pathological MRE11-dependent fork degradation in BRCA2-deficient cells. Chemical-genetic CDC7 inhibition, DNA fiber assays, MRE11 localization, fork restart assays, co-localization experiments EMBO reports High 32496651
2022 Cryo-EM structures of yeast DDK bound to the MCM double hexamer show that Dbf4 (HBRCT domain) anchors to Mcm2 as a docking point, DDK binds across the hexamer interface via three Mcm2/Mcm6/Mcm4 N-terminal domains, and this arrangement brings Cdc7 close to Mcm4-NSD (its essential substrate); Dbf4 displaces the NSD from its binding site on Mcm4, facilitating immediate phosphorylation; a Dbf4 inhibitory loop occupies the Cdc7 active center and disengages during kinase conformational changes. Cryo-electron microscopy (cryo-EM), biochemical binding assays, structure-guided analysis Nature communications High 35296675
2022 Cryo-EM analysis of DDK bound to the MCM double hexamer shows Dbf4 HBRCT domain anchors to Mcm2 and bridges across the double-hexamer interface to allow Cdc7 to phosphorylate Mcm4 on the opposite hexamer; rotation of DDK along the anchor point enables sequential phosphorylation of Mcm2 and Mcm6. Cryo-electron microscopy (cryo-EM), biochemical phosphorylation assays Nature communications High 35614055

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2014 Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes & development 181 24532715
1999 Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. The EMBO journal 181 10523313
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
2008 Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell 150 19013276
2002 Cdc7 kinase complex: a key regulator in the initiation of DNA replication. Journal of cellular physiology 146 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
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
1995 hsk1+, a Schizosaccharomyces pombe gene related to Saccharomyces cerevisiae CDC7, is required for chromosomal replication. The EMBO journal 133 7621824
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
2008 Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes & development 113 18245450
2006 Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells. Molecular biology of the cell 110 16899510
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 109 10465792
1986 Molecular characterization of cell cycle gene CDC7 from Saccharomyces cerevisiae. Molecular and cellular biology 108 3537706
2009 Incorporation into the prereplicative complex activates the Mcm2-7 helicase for Cdc7-Dbf4 phosphorylation. Genes & development 107 19270162
2013 CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Annals of neurology 104 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
1998 Purification of Hsk1, a minichromosome maintenance protein kinase from fission yeast. The Journal of biological chemistry 98 9705352
2000 The pharmacology of hSK1 Ca2+-activated K+ channels expressed in mammalian cell lines. British journal of pharmacology 94 10683185
1999 A fission yeast gene, him1(+)/dfp1(+), encoding a regulatory subunit for Hsk1 kinase, plays essential roles in S-phase initiation as well as in S-phase checkpoint control and recovery from DNA damage. Molecular and cellular biology 94 10409743
2003 Hsk1-Dfp1 is required for heterochromatin-mediated cohesion at centromeres. Nature cell biology 93 14625560
2020 Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair. Nature communications 91 32355159
1992 Temperature-sensitive cdc7 mutations of Saccharomyces cerevisiae are suppressed by the DBF4 gene, which is required for the G1/S cell cycle transition. Genetics 91 1592236
2001 Regulation of initiation of S phase, replication checkpoint signaling, and maintenance of mitotic chromosome structures during S phase by Hsk1 kinase in the fission yeast. Molecular biology of the cell 87 11359920
1997 CDC45 is required in conjunction with CDC7/DBF4 to trigger the initiation of DNA replication. Proceedings of the National Academy of Sciences of the United States of America 86 9356482
2007 Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene 78 18084324
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
2012 Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorganic & medicinal chemistry letters 76 22560567
2006 Cdc7 is an active kinase in human cancer cells undergoing replication stress. The Journal of biological chemistry 73 17062569
2003 The Cdc23 (Mcm10) protein is required for the phosphorylation of minichromosome maintenance complex by the Dfp1-Hsk1 kinase. Proceedings of the National Academy of Sciences of the United States of America 73 12604790
1991 A role for CDC7 in repression of transcription at the silent mating-type locus HMR in Saccharomyces cerevisiae. Molecular and cellular biology 73 1990268
1999 Cell cycle regulation of Dfp1, an activator of the Hsk1 protein kinase. Proceedings of the National Academy of Sciences of the United States of America 72 10411894
2022 CDC7-independent G1/S transition revealed by targeted protein degradation. Nature 70 35508654
2005 Schizosaccharomyces pombe Swi1, Swi3, and Hsk1 are components of a novel S-phase response pathway to alkylation damage. Molecular and cellular biology 70 15767681
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) 65 19815406
2008 The Hsk1(Cdc7) replication kinase regulates origin efficiency. Molecular biology of the cell 63 18799612
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
2009 Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry. Molecular cell 61 19647517
2018 Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication. Molecular cell 60 30392930
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 Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. The Journal of biological chemistry 55 19692334
2009 Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. The Journal of biological chemistry 55 19864417
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
2005 Hsk1-Dfp1/Him1, the Cdc7-Dbf4 kinase in Schizosaccharomyces pombe, associates with Swi1, a component of the replication fork protection complex. The Journal of biological chemistry 52 16263721
2003 Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development. Mutation research 52 14643427
2019 Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor. Science advances 51 31131319
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
2006 Chemical inactivation of cdc7 kinase in budding yeast results in a reversible arrest that allows efficient cell synchronization prior to meiotic recombination. Genetics 48 17057233
2003 Xenopus Drf1, a regulator of Cdc7, displays checkpoint-dependent accumulation on chromatin during an S-phase arrest. The Journal of biological chemistry 48 12897072
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
2000 Byr4 localizes to spindle-pole bodies in a cell cycle-regulated manner to control Cdc7 localization and septation in fission yeast. The Journal of biological chemistry 46 10799520
2009 Interactions between Swi1-Swi3, Mrc1 and S phase kinase, Hsk1 may regulate cellular responses to stalled replication forks in fission yeast. Genes to cells : devoted to molecular & cellular mechanisms 45 19422421
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
2014 MiR-630 inhibits proliferation by targeting CDC7 kinase, but maintains the apoptotic balance by targeting multiple modulators in human lung cancer A549 cells. Cell death & disease 42 25255219
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
2007 Structural changes in Mcm5 protein bypass Cdc7-Dbf4 function and reduce replication origin efficiency in Saccharomyces cerevisiae. Molecular and cellular biology 41 17724082
2017 p53 gain-of-function mutations increase Cdc7-dependent replication initiation. EMBO reports 40 28887320
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
2010 Hsk1- and SCF(Pof3)-dependent proteolysis of S. pombe Ams2 ensures histone homeostasis and centromere function. Developmental cell 38 20230746
2003 Cdc7 kinases (DDKs) and checkpoint responses: lessons from two yeasts. Mutation research 38 14643426
2006 Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast. Proceedings of the National Academy of Sciences of the United States of America 37 16698922
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 32 34663432
2022 The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer. Nature communications 31 35614055
2013 MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung cancer cells. Oncogenesis 31 23877787
2013 Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint. Cell cycle (Georgetown, Tex.) 30 23598722
1999 CDC7 kinase complex as a molecular switch for DNA replication. Frontiers in bioscience : a journal and virtual library 30 10577390
2022 Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase. Nature communications 29 35296675
2010 Hsk1 kinase and Cdc45 regulate replication stress-induced checkpoint responses in fission yeast. Cell cycle (Georgetown, Tex.) 29 21099360
2017 DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors. ACS chemical biology 28 28560864
2020 CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage. EMBO reports 27 32496651
2018 Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML. Scientific reports 27 30361682
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
2008 The role of the Saccharomyces cerevisiae Cdc7-Dbf4 complex in the replication checkpoint. Gene 27 18372119
2005 Dual role of the Cdc7-regulatory protein Dbf4 during yeast meiosis. The Journal of biological chemistry 27 16319063
2013 N-substituted azaindoles as potent inhibitors of Cdc7 kinase. Bioorganic & medicinal chemistry letters 26 23481650
2008 Inhibition of Cdc7/Dbf4 kinase activity affects specific phosphorylation sites on MCM2 in cancer cells. Journal of cellular biochemistry 26 18286467
2006 Importin-beta mediates Cdc7 nuclear import by binding to the kinase insert II domain, which can be antagonized by importin-alpha. The Journal of biological chemistry 26 16492669
1988 CDC7-dependent protein kinase activity in yeast replicative-complex preparations. Proceedings of the National Academy of Sciences of the United States of America 25 3281161