Affinage

DBF4

Protein DBF4 homolog A · UniProt Q9UBU7

Length
674 aa
Mass
76.9 kDa
Annotated
2026-06-09
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DBF4 is the cell-cycle-regulated activating subunit of the Dbf4-dependent kinase (DDK), partnering with the CDC7 catalytic kinase to trigger the initiation of eukaryotic DNA replication (PMID:8474449, PMID:1592236, PMID:10373557). Crystallographic and cryo-EM analyses show DBF4 wraps around CDC7, with its effector motif C stabilizing the kinase αC helix and motif M tethering the C-lobe to support catalytic activity (PMID:23064647, PMID:12694534). DBF4 functions as the targeting subunit of the complex: it binds tightly to Mcm2 and recruits the weakly-associating CDC7 to the MCM2-7 helicase ring, where the assembled, origin-DNA-linked pre-replicative complex becomes the preferred substrate (PMID:19692334, PMID:19270162, PMID:15222894). DDK docks onto one MCM hexamer via the DBF4 HBRCT/docking domain anchored at Mcm2 and phosphorylates the N-terminal tails of Mcm4 (and Mcm2/Mcm6) on the opposed hexamer (PMID:34963704, PMID:35614055, PMID:35296675). The essential function of this phosphorylation is to relieve the inhibitory N-terminal serine/threonine-rich domain of Mcm4 (PMID:20054399); phosphorylation weakens the Mcm2-Mcm5 gate to promote ring opening and ssDNA extrusion, and creates phosphopeptide marks read by Sld3, which recruits Cdc45 and enables GINS loading to assemble the CMG helicase (PMID:25471369, PMID:26912723). DBF4 is also targeted to early origins through direct interaction with forkhead transcription factors Fkh1/Fkh2 and accumulates at kinetochores via the Ctf19 complex to advance pericentromeric origin firing and cohesin loading (PMID:29330352, PMID:23746350). Beyond replication, DDK phosphorylates Mer2 and Rec8 to drive meiotic recombination and cohesin cleavage, recruits the monopolin complex for reductional segregation, and activates the Mus81-Mms4 resolvase in mitosis (PMID:18245450, PMID:20230747, PMID:19013276, PMID:28096179). DBF4 is itself an integration point for DNA-damage signaling: it is directly phosphorylated by ATM/ATR and by Rad53 to inhibit DDK and block late origin firing during the checkpoint (PMID:20835227, PMID:22123827, PMID:34963704), while its own stability is controlled by APC/C-mediated degradation in G1 (PMID:10805723).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1989 Medium

    Established that DBF4 expression is itself cell-cycle controlled, hinting it acts at a defined window of the division cycle.

    Evidence Northern blot of synchronized yeast showing transcript peaking late in G1 with DNA synthesis genes

    PMID:2644125

    Open questions at the time
    • Transcript timing does not establish protein function
    • No mechanism linking Dbf4 to replication yet
  2. 1992 High

    Resolved whether CDC7 and DBF4 act together by showing reciprocal allele-specific genetic suppression, placing both at a common replication-initiation step.

    Evidence Multicopy suppression / epistasis analysis in S. cerevisiae

    PMID:1592236

    Open questions at the time
    • Genetics alone did not define the biochemical relationship
    • No physical complex demonstrated
  3. 1993 High

    Defined Dbf4 as the obligate activating subunit of Cdc7 kinase, framing it as a cyclin-like regulator.

    Evidence In vitro kinase reconstitution, yeast two-hybrid, and thermolabile ts-mutant kinase analysis

    PMID:8474449

    Open questions at the time
    • Substrates of the active kinase unknown
    • No structural basis for activation
  4. 1994 Medium

    Addressed how DDK reaches its site of action by showing Dbf4 associates with origin (ARS) DNA in vivo.

    Evidence One-hybrid and two-hybrid protein-DNA/protein interaction assays in yeast

    PMID:8066465

    Open questions at the time
    • Direct DNA binding vs. indirect recruitment not distinguished
    • No identification of the bridging proteins
  5. 1997 High

    Identified MCM proteins as DDK substrates, linking the kinase to the replicative helicase and to S-phase entry.

    Evidence In vitro kinase assays, dbf4 suppressor of mcm2-1, and co-immunoprecipitation in yeast

    PMID:9407029

    Open questions at the time
    • Functional consequence of MCM phosphorylation undefined
    • Specific essential phosphosites not mapped
  6. 1999 High

    Demonstrated conservation to humans, establishing HsDbf4/ASK as the essential activator of huCdc7 required for replication initiation and the G1/S transition.

    Evidence Co-expression reconstitution, immunodepletion, MCM2 phosphopeptide mapping, antibody microinjection in human cells

    PMID:10373557 PMID:10523313

    Open questions at the time
    • In vivo essential MCM2 sites not yet pinpointed
    • Regulation of human complex by checkpoints unaddressed
  7. 1999 Medium

    Connected DDK to checkpoint kinase Rad53, showing Rad53 binds Dbf4 and supports DBF4 levels and S-phase function separably from checkpoint signaling.

    Evidence Two-hybrid, expression analysis, and separation-of-function rad53 allele in yeast

    PMID:10049915

    Open questions at the time
    • Direction of regulation (positive vs inhibitory) not fully resolved
    • Whether interaction is direct phosphorylation not shown here
  8. 2000 Medium

    Placed DDK in the initiation hierarchy downstream of S-CDK and revealed APC/C-mediated Dbf4 instability as a layer of control.

    Evidence Cell synchronization, kinase assays, in vitro phosphorylation of Cdc45, genetic epistasis in yeast

    PMID:10805723

    Open questions at the time
    • Functional importance of Cdc45 phosphorylation not established
    • APC/C degron on Dbf4 not mapped
  9. 2006 High

    Showed how DDK substrate specificity is achieved through dedicated docking domains and that DDK promotes the stable Cdc45-MCM complex on chromatin.

    Evidence Chromatin fractionation and in vitro kinase assays with purified DDK and a Mcm4 DDK-docking domain

    PMID:17018296

    Open questions at the time
    • How docking dictates phospho-site choice structurally unresolved
    • Link to helicase activation step still indirect
  10. 2006 High

    Defined functionally essential human MCM2 phosphosites and additional DDK substrates, extending the mechanism to chromatin assembly.

    Evidence siRNA rescue with phospho-mutants, in vitro ATPase assay, mass spectrometry (MCM2); Co-IP/kinase/depletion for CAF1 p150 in human cells

    PMID:16826239 PMID:16899510

    Open questions at the time
    • Whether ATPase enhancement directly drives initiation untested
    • In vivo significance of CAF1 phosphorylation not genetically validated
  11. 2008 High

    Expanded DDK function into meiosis, establishing it as a direct kinase for recombination initiation and chromosome segregation distinct from its replication role.

    Evidence Analog-sensitive Cdc7 chemical genetics, Mer2 priming/phosphosite mutagenesis, monopolin localization, and meiotic assays in yeast

    PMID:18245450 PMID:18768747 PMID:19013276

    Open questions at the time
    • Direct monopolin (Lrs4) phosphosites not all mapped
    • Coordination with CDK priming in vivo partly inferred
  12. 2008 Medium

    Probed the DDK-checkpoint relationship, indicating DDK feeds into Rad53/ATR-Chk1 signaling and is itself a Chk1 substrate, with overexpression overriding the S checkpoint.

    Evidence In vitro kinase assays, conditional mutants, and Dbf4 overexpression checkpoint-abrogation in yeast and human cells

    PMID:17276990 PMID:18372119

    Open questions at the time
    • Whether DDK activates or is inhibited by the checkpoint appeared context-dependent
    • Direct phosphosites on Rad53/Dbf4 not mapped here
  13. 2009 High

    Established Dbf4 as the recruiting subunit and showed that incorporation of MCM into the origin-bound pre-RC creates the conformationally preferred DDK substrate.

    Evidence In vitro reconstitution with purified DDK, binding assays, MCM2 phosphosite mutagenesis with bob1 bypass, and pre-RC assembly assays in yeast

    PMID:19270162 PMID:19692334

    Open questions at the time
    • Structural basis of conformational selectivity unresolved
    • How phosphorylation translates into helicase activation still pending
  14. 2010 High

    Defined the essential function of DDK as relief of the Mcm4 NSD inhibitory domain, providing the conceptual bypass logic for replication initiation.

    Evidence mcm4 NSD-deletion plus CDK-bypass genetic epistasis and checkpoint assays in yeast

    PMID:20054399

    Open questions at the time
    • Molecular mechanism by which NSD inhibits unknown at this point
    • Downstream readers of phosphorylation not yet identified
  15. 2010 High

    Established the checkpoint braking mechanism: Rad53 directly phosphorylates Dbf4 (and Sld3) to redundantly block late origin firing while preserving CDK activity.

    Evidence Genetic epistasis, in vitro phosphorylation, and phosphomimetic mutants in S. cerevisiae

    PMID:20835227

    Open questions at the time
    • Structural mechanism of Dbf4 inhibition not yet shown
    • Relative contribution of Dbf4 vs Sld3 arm context-dependent
  16. 2010 High

    Extended DDK meiotic substrates to Rec8, establishing it as a direct regulator of cohesin cleavage by separase in meiosis I.

    Evidence Chemical genetic inhibition and phosphomimetic Rec8 rescue in meiotic division assays in yeast

    PMID:20230747

    Open questions at the time
    • Centromeric protection mechanism not fully defined
    • Division of labor between DDK and CK1 not quantified
  17. 2010 Medium

    Mapped distinct Dbf4 regulatory surfaces, separating the Rad53-interacting motif N, the Mcm2-binding motif M, and the origin/Mcm2-engaging motif C zinc finger.

    Evidence Domain deletion/point mutants with Co-IP, ChIP, kinase and genotoxic sensitivity assays in yeast; non-canonical PBD interaction with Cdc5

    PMID:16107698 PMID:20436286 PMID:21036905

    Open questions at the time
    • Structural definition of these motifs still lacking at this stage
    • Functional consequence of the Cdc5-Dbf4 interaction underexplored
  18. 2012 High

    Delivered the structural basis of activation, showing how Dbf4 wraps CDC7 and how motifs C and M stabilize and tether the kinase.

    Evidence X-ray crystallography of human CDC7-DBF4 with nucleotide/inhibitor

    PMID:23064647

    Open questions at the time
    • Structure did not include MCM substrate engagement
    • Did not explain origin-targeting or checkpoint inhibition
  19. 2013 High

    Defined the MCM docking architecture (Dbf4-Mcm2, Cdc7-Mcm4/5) and kinetochore-directed origin/cohesin functions, and linked DDK to translesion repair via RAD18.

    Evidence Two-hybrid/Co-IP with synthetic lethality, live imaging/ChIP with ctf19 mutants, and RAD18 domain-mapping/chromatin-loading assays

    PMID:23549044 PMID:23746350 PMID:24240236

    Open questions at the time
    • Stoichiometry of dual docking unresolved
    • Generality of kinetochore-directed firing across organisms unknown
  20. 2014 High

    Provided the mechanistic link from phosphorylation to helicase activation: DDK weakens Mcm2-Mcm5, opens the ring, extrudes ssDNA, and triggers GINS attachment.

    Evidence In vitro kinase, ssDNA extrusion, and GINS-Mcm2-7 interaction assays plus in vivo S-phase analysis

    PMID:25471369

    Open questions at the time
    • How Cdc45 is coordinated with this step not addressed here
    • Order of ring opening vs phosphopeptide reading unresolved
  21. 2016 High

    Identified Sld3 as the essential reader of DDK phosphomarks on Mcm4/Mcm6 that bridges to Cdc45 recruitment, completing the phospho-signal relay.

    Evidence Reconstitution with purified proteins, phosphopeptide binding, phosphomimetic bypass, and in vitro replication assays

    PMID:26912723

    Open questions at the time
    • Structural detail of Sld3-phosphopeptide recognition pending
    • How reading is coupled to ring opening not integrated
  22. 2017 High

    Extended mitotic and repair roles by establishing DDK as a required activator of the Mus81-Mms4 resolvase and a kinase for HSP90 supporting recombination repair.

    Evidence Co-IP, in vitro kinase assays, and genetic analysis (Mus81-Mms4/Rtt107) in yeast; phosphoproteomics/functional repair assays (HSP90) in human cells

    PMID:28096179 PMID:29209046

    Open questions at the time
    • Interplay of DDK and Cdc5 ordering at Mus81 not fully resolved
    • In vivo importance of HSP90 Ser-164 site not genetically isolated
  23. 2018 High

    Explained spatial control of origin timing, showing Dbf4's C-terminus directly binds forkhead factors Fkh1/Fkh2 to enrich DDK at early origins and recruit limiting factors via Sld3.

    Evidence ChIP-seq, in vitro interaction reconstitution, dbf4ΔC mutant analysis, and genome-wide replication profiling in yeast

    PMID:29330352

    Open questions at the time
    • Whether forkhead-mediated targeting operates in metazoa unknown
    • Structural basis of Dbf4-Fkh interaction undefined
  24. 2022 High

    Provided high-resolution structural mechanism of substrate engagement: Dbf4 anchors to Mcm2 across the hexamer interface, positions Cdc7 to phosphorylate the opposed Mcm4/2/6 tails, displaces the Mcm4 NSD, and uses an inhibitory loop disengaged by kinase wobbling; Rad53 phosphorylation blocks DH binding.

    Evidence Cryo-EM of yeast DDK on MCM double hexamer with biochemical and truncation validation

    PMID:34963704 PMID:35296675 PMID:35614055

    Open questions at the time
    • Dynamics of the wobbling/inhibitory loop transition not kinetically resolved
    • Human DDK-MCM structural details extrapolated from yeast

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the conserved replication-initiation machinery is reconciled with reported replication-independent roles of vertebrate Dbf4 in development remains unresolved.
  • Whether the developmental Wnt role generalizes beyond Xenopus is unknown
  • Division of labor between DBF4 and DRF1/ASKL1 in human cells not defined
  • No structural/mechanistic account of non-Cdc7 functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 4 GO:0003677 DNA binding 2
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 1
Pathway
R-HSA-69306 DNA Replication 5 R-HSA-73894 DNA Repair 5 R-HSA-1474165 Reproduction 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1640170 Cell Cycle 3
Partners
CDC5CDC7FKH1MCM2MCM4RAD18RAD53SLD3
Complex memberships
Dbf4-dependent kinase (DDK / Cdc7-Dbf4)

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Dbf4 protein is required for Cdc7 kinase activity; in vitro reconstitution and two-hybrid assays demonstrated that Cdc7 and Dbf4 interact both in vitro and in vivo, and Cdc7 kinase activity is thermolabile in extracts from a temperature-sensitive dbf4 mutant, establishing Dbf4 as the activating subunit (proposed as a cyclin-like activator) of Cdc7 kinase. In vitro kinase reconstitution, yeast two-hybrid, temperature-sensitive mutant analysis Molecular and cellular biology High 8474449
1989 DBF4 transcript is cell cycle regulated, peaking late in G1 coincident with genes involved in DNA synthesis, establishing that Dbf4 expression oscillates during the cell cycle. Northern blot / cell cycle synchronization Experimental cell research Medium 2644125
1992 Genetic epistasis analysis showed that CDC7 and DBF4 act at a common point in the cell cycle for initiation of DNA replication; multicopy DBF4 suppresses cdc7 temperature-sensitive mutations in an allele-specific manner, and multicopy CDC7 suppresses dbf4 mutations, indicating functional interdependence. Genetic suppression / epistasis analysis in S. cerevisiae Genetics High 1592236
1994 Dbf4 protein interacts directly with yeast replication origins (ARS sequences) in vivo, suggesting that one function of Dbf4 is to recruit Cdc7 kinase to initiation complexes at origins. One-hybrid and two-hybrid assays for protein-DNA and protein-protein interactions in vivo Science (New York, N.Y.) Medium 8066465
1997 Cdc7-Dbf4 physically interacts with Mcm2 and phosphorylates Mcm2 and three other MCM2-7 family members (Mcm3, Mcm4, Mcm6) in vitro; a dbf4 suppressor mutation of mcm2-1 restores S-phase entry, establishing MCM proteins as substrates of DDK and linking DDK-dependent MCM phosphorylation to initiation of DNA synthesis. In vitro kinase assay, genetic suppressor screen, co-immunoprecipitation Genes & development High 9407029
1999 Human Dbf4 homolog (HsDbf4/ASK) binds HsCdc7 and activates its kinase activity when co-expressed; purified HsCdc7-HsDbf4 selectively phosphorylates MCM2 in vitro, and 2D tryptic phosphopeptide mapping shows comigration of in vitro and in vivo MCM2 phosphopeptides; microinjection of anti-HsCdc7 antibodies blocks DNA replication initiation in HeLa cells. Co-expression in insect/mammalian cells, in vitro kinase assay, 2D phosphopeptide mapping, antibody microinjection The EMBO journal High 10523313
1999 Human ASK (Dbf4 homolog) was identified as the major activator of huCdc7; immunodepletion of ASK from cell extracts abolished huCdc7-dependent kinase activity; ASK forms an active kinase complex with huCdc7 that phosphorylates MCM2; ASK protein levels peak during S phase; microinjection of ASK-specific antibodies inhibited DNA replication, establishing ASK as an essential cyclin-like regulatory subunit required for G1/S transition. Immunodepletion, in vitro kinase assay, cell cycle synchronization, antibody microinjection Molecular and cellular biology High 10373557
1998 S-CDK (Dbf4/Cdc7) kinase and Mcm proteins are required for RPA association with replication origins; early- and late-firing origins differ in the timing of RPA recruitment rather than Mcm loading, and Rad53 kinase prevents RPA association with late origins under replication stress, placing DDK as a regulator of origin unwinding upstream of RPA loading. Chromatin immunoprecipitation (ChIP) at ARS sequences in yeast with conditional mutants The EMBO journal Medium 9724654
2000 Dbf4 protein is unstable throughout the cell cycle and is degraded by the APC/C in G1; DDK function for DNA replication requires prior S-CDK activation (i.e., DDK acts downstream of S-CDKs in the replication initiation hierarchy); Cdc45 is phosphorylated by DDK in vitro, suggesting it as a critical DDK substrate after S-CDK activation. Cell synchronization, kinase activity assays, in vitro phosphorylation, genetic epistasis Molecular and cellular biology Medium 10805723
1999 RAD53 positively regulates DBF4: two-hybrid analysis shows Rad53p binds Dbf4p; steady-state DBF4 mRNA and Dbf4p protein levels are reduced in rad53 mutant strains; a rad53 allele (rad53-31) retains checkpoint function but loses the DNA replication function, demonstrating that Rad53's checkpoint and replication functions can be genetically separated and that Rad53 activates S phase through Dbf4. Yeast two-hybrid, Northern/Western blot analysis, genetic allele analysis Genetics Medium 10049915
2006 Cdc7-Dbf4 promotes assembly of a stable Cdc45-MCM complex exclusively on chromatin in S phase; DDK hyperphosphorylates Mcm4 at its N-terminus in vitro; specificity of DDK substrate targeting is conferred by an adjacent DDK-docking domain (DDD) in Mcm4 that facilitates phosphorylation in cis. Chromatin fractionation, in vitro kinase assay with purified DDK and Mcm4, genetic analysis Molecular cell High 17018296
2006 Human Cdc7/Dbf4 phosphorylates MCM2 at specific sites (Ser-108 and Ser-40) in vitro and in vivo; phosphomimetic MCM2 (MCM2E) rescues DNA replication after MCM2 siRNA knockdown while non-phosphorylatable MCM2 (MCM2A) does not; phosphomimetic MCM2E-7 complex shows higher ATPase activity than MCM2A-7, establishing that Cdc7/Dbf4 phosphorylation of MCM2 is essential for replication initiation in mammalian cells. siRNA knockdown, phosphomimetic/non-phosphorylatable mutant rescue, in vitro ATPase assay, mass spectrometry Molecular biology of the cell High 16899510
2006 Cdc7-Dbf4 directly phosphorylates the p150 (large) subunit of chromatin assembly factor 1 (CAF1) in vitro; this phosphorylation changes p150 oligomerization state and promotes binding to PCNA; CAF1 recruitment is reduced in Cdc7-depleted extracts, establishing a link between DDK and chromatin assembly during DNA replication. Co-immunoprecipitation, in vitro kinase assay, PCNA/DNA loading assay, Cdc7 depletion EMBO reports Medium 16826239
2007 Dbf4 interacts weakly with Chk1 in vivo 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 DDK as a target of the ATR-Chk1 S checkpoint in human cells. Co-immunoprecipitation, in vitro kinase assay, Dbf4 overexpression checkpoint abrogation assay The Journal of biological chemistry Medium 17276990
2008 Cdc7-Dbf4 (DDK) promotes double-strand break (DSB) formation for meiotic recombination and recruits the monopolin complex to kinetochores for monopolar attachment, the latter likely through phosphorylation of the monopolin subunit Lrs4; these functions are independent of DDK's role in initiating DNA replication. Chemical genetic kinase inhibition in yeast, monopolin localization assays, meiotic recombination assays Cell High 19013276
2008 CDK-S (Cdc28-Clb5) phosphorylates Mer2 at Ser30, which primes Mer2 for subsequent DDK (Cdc7-Dbf4) phosphorylation at Ser29; this sequential phosphorylation creates a negatively charged patch required for meiotic DSB formation. In vitro kinase assay, phosphomimetic/non-phosphorylatable mutants, genetic analysis in yeast Genes & development High 18245450
2008 Cdc7-Dbf4 kinase activity is required for full activation of Rad53 in response to replication stress; recombinant Cdc7-Dbf4 phosphorylates Rad53 in vitro; in Cdc7-Dbf4-deficient cells, Rad53 remains hypophosphorylated, anaphase spindle elongates, and checkpoint transcription is not induced. In vitro kinase assay, conditional mutant analysis, Rad53 autophosphorylation assay Gene Medium 18372119
2008 Cdc7-Dbf4 has a role in NDT80 transcription activation and in monopolin recruitment to kinetochores for reductional segregation in meiosis I; demonstrated using an analog-sensitive Cdc7 allele. Chemical genetic approach (analog-sensitive allele), transcription and chromosome segregation assays Molecular biology of the cell Medium 18768747
2009 Dbf4 forms a heterodimer with Cdc7 with substantially higher specific activity toward Mcm2 than Cdc7 alone; Dbf4 alone binds tightly to Mcm2 while Cdc7 alone binds weakly, establishing that Dbf4 recruits Cdc7 to phosphorylate Mcm2; DDK phosphorylates Mcm2 at Ser-164 and Ser-170, and expression of mcm2-S170A is lethal in cells lacking endogenous MCM2 but rescued by the DDK bypass mcm5-bob1 mutation. In vitro kinase assay, binding assay, yeast genetics/lethality rescue The Journal of biological chemistry High 19692334
2009 Incorporation of Mcm2-7 into the pre-RC on origin DNA increases the level and changes the specificity of DDK phosphorylation; DDK tightly associates with Mcm2-7 in a Dbf4-dependent manner and preferentially targets a conformationally distinct, origin-DNA-linked subpopulation; DDK association requires prior phosphorylation of the pre-RC. In vitro pre-RC assembly with purified proteins, kinase assay, origin DNA binding assays Genes & development High 19270162
2009 LEDGF interacts with Cdc7-ASK (Dbf4) heterodimer; the interaction requires autophosphorylation of the kinase and 50 C-terminal residues of ASK; LEDGF is phosphorylated by the kinase at Ser-206; LEDGF potently stimulates Cdc7-ASK kinase activity (>10-fold increase in MCM2 phosphorylation in vitro) by relieving autoinhibition imposed by the ASK C-terminus. Co-immunoprecipitation from human cell extracts, truncation analysis, in vitro kinase assay The Journal of biological chemistry Medium 19864417
2010 The checkpoint kinase Rad53 inhibits DDK by directly phosphorylating Dbf4, and inhibits CDK-dependent replication by phosphorylating Sld3; these act redundantly to block origin firing during the S-phase checkpoint while CDK remains active to prevent Mcm2-7 re-loading. Genetic epistasis, in vitro phosphorylation, phosphomimetic mutants in S. cerevisiae Nature High 20835227
2010 The sole essential function of DDK (Dbf4-Cdc7) in S. cerevisiae is to relieve an inhibitory activity residing within the N-terminal serine/threonine-rich domain (NSD) of Mcm4; when an mcm4 mutant lacking the NSD inhibitory domain is combined with CDK bypass mutations, DNA synthesis can occur in G1 without DDK; DDK is also required for intra-S-phase checkpoint activation. Genetic epistasis, mcm4 NSD deletion mutants, CDK bypass mutations, checkpoint assays in yeast Nature High 20054399
2010 Multiple phosphorylation sites within Rec8 and two kinases—CK1δ/ε and DDK (Dbf4-dependent Cdc7)—are required for Rec8 cleavage by separase and meiosis I nuclear division; phosphomimetic Rec8 is no longer protected at centromeres and is cleaved even when kinases are inhibited, establishing DDK as a direct regulator of cohesin cleavage in meiosis. Chemical genetic kinase inhibition, phosphomimetic mutants, meiosis I division assays Developmental cell High 20230747
2010 Dbf4 interacts with Cdc5 polo-like kinase via a non-canonical polo-box domain (PBD) binding site at the Dbf4 N-terminus; Dbf4 inhibits Cdc5 function through direct binding; the PBD-Dbf4 interaction occurs via a distinct PBD surface from phosphoprotein binding. Yeast two-hybrid, co-immunoprecipitation, genetic analysis with dbf4 and cdc5 mutants The Journal of biological chemistry Medium 21036905
2011 ATM and ATR directly phosphorylate Dbf4 in response to ionizing radiation and replication stress; ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication; DDK kinase activity (not suppressed by damage) is required for fork protection under replication stress. In vitro kinase assay with ATM/ATR, phosphorylation site mutagenesis, S-phase checkpoint assays in mammalian cells The Journal of biological chemistry High 22123827
2012 Crystal structure of human CDC7-DBF4 complex reveals DBF4 wraps around CDC7 burying ~6,000 Ų of hydrophobic surface; the DBF4 effector domain (motif C) binds the CDC7 N-terminal lobe and stabilizes the αC helix to support kinase activity; DBF4 motif M latches onto the CDC7 C-terminal lobe as a tethering domain. X-ray crystallography of human CDC7-DBF4 complex with nucleotide and inhibitor-bound forms Nature structural & molecular biology High 23064647
2013 ATR-Chk1 signaling stabilizes the Cdc7-ASK (Dbf4) complex upon replication block by inactivating APC/C(Cdh1) through Cdh1 degradation; motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for RAD18 chromatin binding, RAD18 foci formation, and loading of translesion polymerase η. Co-immunoprecipitation, domain mapping, RAD18 foci assay, chromatin loading assay in human cells Genes & development High 24240236
2013 Dbf4 interacts with Mcm2 via an N-terminal Mcm2 region (DDK docking domain), while Cdc7 interacts with Mcm4 and Mcm5; combining Mcm2ΔDDD and Mcm4ΔDDD mutations is synthetically lethal, establishing that Mcm2 and Mcm4 play overlapping roles in DDK docking at MCM rings at replication origins. Two-hybrid and Co-IP, synthetic lethality analysis, domain truncation mutants in yeast The Journal of biological chemistry Medium 23549044
2013 DDK accumulates at kinetochores in telophase facilitated by the Ctf19 kinetochore complex; kinetochore-localized DDK promptly recruits Sld3-Sld7 to pericentromeric origins for early S-phase replication; DDK at kinetochores independently recruits the Scc2-Scc4 cohesin loader to centromeres in G1, enhancing cohesin loading and pericentromeric cohesion. Live-cell imaging, ChIP, genetic analysis with ctf19 mutants in yeast Molecular cell High 23746350
2014 DDK phosphorylation of Mcm2 weakens the Mcm2-Mcm5 interaction and promotes Mcm2-7 ring opening in vitro; ring opening allows ssDNA extrusion from the Mcm2-7 central channel, which triggers GINS attachment to Mcm2-7, providing a mechanistic link between DDK phosphorylation and CMG helicase assembly. In vitro kinase assay, ssDNA extrusion assay, GINS-Mcm2-7 interaction assay, in vivo S-phase analysis The Journal of biological chemistry High 25471369
2016 Sld3 is an essential 'reader' of DDK phosphorylation: Sld3 is recruited to the MCM double hexamer in a DDK-dependent manner by binding specifically to DDK-phosphorylated peptides from Mcm4 and Mcm6; Sld3 then recruits Cdc45; phosphomimetic mutants of Mcm4 and Mcm6 bind Sld3 without DDK and support DDK-independent replication. Biochemical reconstitution with purified proteins, phosphopeptide binding assays, phosphomimetic mutants, in vitro replication assay The EMBO journal High 26912723
2017 DDK (Cdc7-Dbf4) targets Mus81-Mms4 together with Cdc5; both kinases bind and phosphorylate Mus81-Mms4 in an interdependent manner; DDK-mediated phosphorylation of Mms4 is strictly required for Mus81 activation in mitosis; scaffold protein Rtt107 binds Mus81-Mms4 and interacts with Cdc7, tethering DDK and Cdc5 to enable full Mus81 activation. Co-immunoprecipitation, in vitro kinase assay, genetic analysis in yeast The EMBO journal High 28096179
2018 Dbf4 is enriched at early replication origins through direct interaction with forkhead transcription factors Fkh1/Fkh2 via its C-terminus; this interaction was reconstituted in vitro; a dbf4ΔC interaction-defective mutant phenocopies fkh alleles; Dbf4 also interacts directly with Sld3 and promotes recruitment of downstream limiting replication factors. ChIP-seq, in vitro protein interaction reconstitution, dbf4 mutant analysis, genome-wide replication profiling Genes & development High 29330352
2021 Cryo-EM structure of S. cerevisiae DDK phosphorylating the MCM double hexamer reveals: DDK docks onto one MCM ring via the Dbf4 docking domain and phosphorylates the opposed ring; truncation of Dbf4 docking domain abrogates DH phosphorylation without affecting Cdc7 activity; Rad53 phosphorylation of Dbf4 impairs DDK binding to DHs and interferes with Cdc7 active site, blocking late origin firing. Cryo-electron microscopy, biochemical phosphorylation assays, domain truncation, Rad53 phosphorylation assay Nature structural & molecular biology High 34963704
2022 Cryo-EM structures of DDK bound to MCM-DH show Dbf4 (via its HBRCT domain) anchors to Mcm2 across the hexamer interface and positions Cdc7 to phosphorylate the N-terminal tails of Mcm4 on the opposite hexamer; rotation of DDK along the anchoring point also allows phosphorylation of Mcm2 and Mcm6; a unique Dbf4 inhibitory loop occupies the Cdc7 active center and is disengaged when the kinase core assumes wobbling conformations. Cryo-electron microscopy, biochemical analysis, domain interaction mapping Nature communications High 35614055
2022 Cryo-EM structures of yeast DDK bound to the MCM-DH show DDK interactions are mediated exclusively by Dbf4 straddling across the hexamer interface on Mcm2, Mcm6, and Mcm4 N-terminal domains; Dbf4 displaces the Mcm4 NSD from its binding site on Mcm4-NTD, facilitating immediate targeting of this motif by Cdc7; an inhibitory Dbf4 loop in the Cdc7 active center is disengaged when the kinase assumes wobbling conformations. Cryo-electron microscopy, biochemical analysis Nature communications High 35296675
2003 Human Cdc7-ASK localization is cell cycle regulated: GFP-ASK accumulates in nuclei at telophase, but chromatin binding peaks only at late G1; nuclear localization requires two NLS sequences (NLS1 and NLS2) in ASK; both Dbf4 motif M and motif C are required for huCdc7 kinase activation; huCdc7 and ASK are independently regulated for nuclear import and chromatin binding. GFP fusion live-cell imaging, nuclear fractionation, truncation/deletion mutant analysis in mammalian cells Genes to cells Medium 12694534
2005 Drf1/ASKL1, a second human Dbf4/ASK-related protein, binds and activates huCdc7; Cdc7-ASKL1 complex phosphorylates MCM2; siRNA depletion of Drf1/ASKL1 delays S phase and causes mitotic retardation. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown with cell cycle analysis The Journal of biological chemistry Medium 15668232
2005 In Xenopus, XDbf4 is required to recruit XCdc7 to chromatin; XDbf4 can bind chromatin independently of pre-RC formation and of XCdc7, while XCdc7 chromatin binding depends on XDbf4; establishing that Dbf4 acts as the chromatin-targeting subunit for Cdc7. Xenopus egg extract cell-free replication assay, chromatin fractionation, immunodepletion BMC molecular biology Medium 15222894
2005 Dbf4 motif N deletion (Dbf4ΔN) disrupts the Dbf4-Rad53 interaction but not Dbf4-Mcm2 association, rendering cells hypersensitive to genotoxic agents; motif M deletion (Dbf4ΔM) abrogates Dbf4-Mcm2 association but not Dbf4-Rad53, impairing cell cycle progression; the dna52-1 point mutation within motif M cannot maintain interactions with Mcm2 or Orc2 at semipermissive temperature. Deletion mutant analysis, Co-IP, genetic sensitivity assays in yeast Molecular and cellular biology Medium 16107698
2004 CDC7 and DBF4 function in the translesion synthesis branch of the RAD6 epistasis group for UV-induced mutagenesis; CDC7 constitutes a pathway separate from RAD5, RAD30, and POL30, but functions in the same pathway as REV3 in response to UV damage. Genetic epistasis analysis using DNA damage sensitivity assays in S. cerevisiae Genetics Medium 15342501
2010 Dbf4 motif C zinc finger is required for Dbf4 association with ARS1 origin DNA and with Mcm2; mutation of conserved motif C cysteines and histidines impairs these interactions and reduces Mcm2 phosphorylation; motif C mutant strains are compromised for S phase entry and progression, and are sensitive to prolonged genotoxic stress. Mutagenesis of motif C, ChIP at ARS1, Co-IP with Mcm2, kinase assay, cell cycle analysis Cell cycle (Georgetown, Tex.) Medium 20436286
2008 Dbf4-Cdc7 (DDK) is not inhibited during the DNA-damage-induced S-phase checkpoint in Xenopus egg extracts or mammalian cells; instead, addition of purified Ddk to Xenopus extracts or overexpression of Dbf4 in HeLa cells downregulates ATR-Chk1 checkpoint signaling and overrides replication inhibition, suggesting DDK acts as an upstream attenuator of checkpoint signaling. Xenopus egg extract assay, HeLa cell Dbf4 overexpression, ATR-Chk1 signaling readouts Molecular cell Medium 19111665
2005 In Xenopus, XDbf4 (a vertebrate Dbf4 homolog) is an inhibitor of canonical Wnt signaling required for heart development; XDbf4 physically and functionally interacts with Frodo, a regulator of Wnt signaling; an XDbf4 mutant that inhibits Wnt signaling but lacks Cdc7-regulating ability restores cardiac markers, demonstrating that Dbf4's role in cardiac development is independent of its cell cycle function. Gain/loss-of-function in Xenopus embryos, protein interaction assays, cardiac marker analysis Developmental cell Medium 15866161
2017 Cdc7-Dbf4 phosphorylates HSP90 at Ser-164 in vitro and in vivo; this phosphorylation stabilizes the HSP90-HCLK2-MRN complex and is required for ATR/ATM signaling and homologous recombination DNA repair under replication stress. Phosphoproteomics, in vitro kinase assay, co-immunoprecipitation, functional DNA repair assays Scientific reports Medium 29209046

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. The EMBO journal 2045 9564042
1990 Cryopreservation of mammalian sperm: what we ask them to survive. Journal of andrology 384 2179184
2006 Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Molecular cell 270 17018296
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
1993 A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Molecular and cellular biology 237 8321244
2010 Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. Nature 227 20835227
1993 Cell cycle regulation of the yeast Cdc7 protein kinase by association with the Dbf4 protein. Molecular and cellular biology 217 8474449
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
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
1998 Association of RPA with chromosomal replication origins requires an Mcm protein, and is regulated by Rad53, and cyclin- and Dbf4-dependent kinases. The EMBO journal 139 9724654
2013 Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment. Molecular cell 119 23746350
2019 Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask). Cells 114 30995798
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
2006 Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells. Molecular biology of the cell 111 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
2016 Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. The EMBO journal 108 26912723
2009 Incorporation into the prereplicative complex activates the Mcm2-7 helicase for Cdc7-Dbf4 phosphorylation. Genes & development 107 19270162
2022 DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation. Journal of neuroinflammation 104 35658977
2007 Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1. The Journal of biological chemistry 103 17210579
2016 Everything we always wanted to know about furosemide but were afraid to ask. American journal of physiology. Renal physiology 100 26911852
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
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
1993 Gene structure and expression of the Corynebacterium flavum N13 ask-asd operon. Journal of bacteriology 87 8100567
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
2008 Everything you wanted to know about small RNA but were afraid to ask. Laboratory investigation; a journal of technical methods and pathology 78 18427554
1989 The yeast gene, DBF4, essential for entry into S phase is cell cycle regulated. Experimental cell research 77 2644125
2019 Ginsenoside Re Inhibits ROS/ASK-1 Dependent Mitochondrial Apoptosis Pathway and Activation of Nrf2-Antioxidant Response in Beta-Amyloid-Challenged SH-SY5Y Cells. Molecules (Basel, Switzerland) 71 31344860
2000 The Cdc7/Dbf4 protein kinase: target of the S phase checkpoint? EMBO reports 68 11269496
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
2000 The modes of action of juvenile hormones: some questions we ought to ask. Insect biochemistry and molecular biology 66 10876109
2017 The regulatory and signaling mechanisms of the ASK family. Advances in biological regulation 65 28669716
2012 Crystal structure of human CDC7 kinase in complex with its activator DBF4. Nature structural & molecular biology 61 23064647
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
1999 The Drosophila chiffon gene is required for chorion gene amplification, and is related to the yeast Dbf4 regulator of DNA replication and cell cycle. Development (Cambridge, England) 57 10477296
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 A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases. The Journal of biological chemistry 56 15668232
2023 Liquid-Liquid Phase Separation? Ask the Water! The journal of physical chemistry letters 55 36745512
2009 Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. The Journal of biological chemistry 55 19692334
2019 Everything You Always Wanted to Know About Salmonella Type 1 Fimbriae, but Were Afraid to Ask. Frontiers in microbiology 54 31139165
2007 ASK family proteins in stress response and disease. Molecular biotechnology 54 17914158
2004 CDC7/DBF4 functions in the translesion synthesis branch of the RAD6 epistasis group in Saccharomyces cerevisiae. Genetics 54 15342501
2005 Dechloromonas hortensis sp. nov. and strain ASK-1, two novel (per)chlorate-reducing bacteria, and taxonomic description of strain GR-1. International journal of systematic and evolutionary microbiology 53 16166710
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 53 16263721
2017 Dbf4-dependent kinase and the Rtt107 scaffold promote Mus81-Mms4 resolvase activation during mitosis. The EMBO journal 52 28096179
2015 Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 51 26003800
2008 The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control. Molecular cell 51 19111665
2018 Dbf4 recruitment by forkhead transcription factors defines an upstream rate-limiting step in determining origin firing timing. Genes & development 47 29330352
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
1999 RAD53 regulates DBF4 independently of checkpoint function in Saccharomyces cerevisiae. Genetics 45 10049915
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
2011 Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint. The Journal of biological chemistry 40 22123827
2013 SCO2 induces p53-mediated apoptosis by Thr845 phosphorylation of ASK-1 and dissociation of the ASK-1-Trx complex. Molecular and cellular biology 39 23319048
2022 Everything You Always Wanted to Know About Organoid-Based Models (and Never Dared to Ask). Cellular and molecular gastroenterology and hepatology 38 35643188
2021 Structural mechanism for the selective phosphorylation of DNA-loaded MCM double hexamers by the Dbf4-dependent kinase. Nature structural & molecular biology 36 34963704
2005 A vertebrate homolog of the cell cycle regulator Dbf4 is an inhibitor of Wnt signaling required for heart development. Developmental cell 35 15866161
2000 The Schizosaccharomyces pombe spo6+ gene encoding a nuclear protein with sequence similarity to budding yeast Dbf4 is required for meiotic second division and sporulation. Genes to cells : devoted to molecular & cellular mechanisms 34 10886372
2013 Dbf4 and Cdc7 proteins promote DNA replication through interactions with distinct Mcm2-7 protein subunits. The Journal of biological chemistry 33 23549044
2010 Dbf4 regulates the Cdc5 Polo-like kinase through a distinct non-canonical binding interaction. The Journal of biological chemistry 33 21036905
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
2023 Mechanism of assembly of type 4 filaments: everything you always wanted to know (but were afraid to ask). Microbiology (Reading, England) 32 36947586
2017 ASK family and cancer. Advances in biological regulation 32 28552579
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
2018 ASK family kinases mediate cellular stress and redox signaling to circadian clock. Proceedings of the National Academy of Sciences of the United States of America 31 29555767
2015 The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response. Science signaling 30 26243192
2022 Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase. Nature communications 29 35296675
2018 Ginsenoside Rb1 protects against spinal cord ischemia-reperfusion injury in rats by downregulating the Bax/Bcl-2 ratio and caspase-3 and p-Ask-1 levels. Experimental and molecular pathology 29 30184471
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
2007 Cell-free assays: the reductionist approach to the study of NADPH oxidase assembly, or "all you wanted to know about cell-free assays but did not dare to ask". Methods in molecular biology (Clifton, N.J.) 29 18453125
2005 A mutation in Dbf4 motif M impairs interactions with DNA replication factors and confers increased resistance to genotoxic agents. Molecular and cellular biology 29 16107698
1999 nimO, an Aspergillus gene related to budding yeast Dbf4, is required for DNA synthesis and mitotic checkpoint control. Journal of cell science 29 10194410
1990 Organelle transformation: shoot first, ask questions later. Trends in biochemical sciences 29 2077686
2016 Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress. Molecular & cellular proteomics : MCP 28 27006476
2016 Concerted activities of Mcm4, Sld3, and Dbf4 in control of origin activation and DNA replication fork progression. Genome research 27 26733669
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
2012 What shall we do with the damaged proteins in lung disease? Ask the proteasome! The European respiratory journal 26 22441749
2011 Regulation of anoxic death in Caenorhabditis elegans by mammalian apoptosis signal-regulating kinase (ASK) family proteins. Genetics 26 21212236
2008 Inhibition of Cdc7/Dbf4 kinase activity affects specific phosphorylation sites on MCM2 in cancer cells. Journal of cellular biochemistry 26 18286467
2014 The Dbf4-Cdc7 kinase promotes Mcm2-7 ring opening to allow for single-stranded DNA extrusion and helicase assembly. The Journal of biological chemistry 25 25471369
2008 Interplay between S-cyclin-dependent kinase and Dbf4-dependent kinase in controlling DNA replication through phosphorylation of yeast Mcm4 N-terminal domain. Molecular biology of the cell 25 18321994
2018 Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach. EBioMedicine 24 30293817
2004 A Xenopus Dbf4 homolog is required for Cdc7 chromatin binding and DNA replication. BMC molecular biology 24 15222894
2022 Empagliflozin mitigates methotrexate-induced hepatotoxicity: Targeting ASK-1/JNK/Caspase-3 pathway. International immunopharmacology 23 36462340
2019 The Thioredoxin System is Regulated by the ASK-1/JNK/p38/Survivin Pathway During Germ Cell Apoptosis. Molecules (Basel, Switzerland) 23 31547465
2009 Potentiation of paclitaxel-induced apoptosis by galectin-13 overexpression via activation of Ask-1-p38-MAP kinase and JNK/SAPK pathways and suppression of Akt and ERK1/2 activation in U-937 human macrophage cells. European journal of cell biology 23 19717209
2009 Differences in the C-terminus contribute to variations in trafficking between rat and human 5-HT(2A) receptor isoforms: identification of a primate-specific tripeptide ASK motif that confers GRK-2 and beta arrestin-2 interactions. Journal of neurochemistry 23 19919577
2021 When to ask for an MRI of the scrotum. Andrology 22 33964115
2017 Ask yeast how to burn your fats: lessons learned from the metabolic adaptation to salt stress. Current genetics 22 28631015
2017 Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer. Scientific reports 22 29209046
2013 Dbf4: the whole is greater than the sum of its parts. Cell cycle (Georgetown, Tex.) 22 23549174
2011 Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. Free radical biology & medicine 22 21557999
2010 The Dbf4 motif C zinc finger promotes DNA replication and mediates resistance to genotoxic stress. Cell cycle (Georgetown, Tex.) 22 20436286
2002 Human Dbf4/ASK promoter is activated through the Sp1 and MluI cell-cycle box (MCB) transcription elements. Oncogene 22 12420215

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