DDK (Cdc7/Hsk plus Dbf4/Dfp1)
Protein kinase required for initiation of DNA replication, probably via phosphorylation of Mcm2-7.
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Cdc7 |
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Synonyms |
SpHsk1 |
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Molecular weight |
58 kDa (Sc) |
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Biochemical properties |
Protein kinase, requires Dbf4 for function (1) (2) Activity stimulated in vitro by polyamines and histones (3) |
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Motifs |
•Kinase • nrs ( needed for localization distinct from nls) (4) |
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Interactions |
Sc • Mcm2-7 proteins (in vitro) (5) in vivo (6) for MCM4 aids its interaction cdc45 (7) •Mcm5/Cdc46 (bob1) mutation can suppress requirement for DDK (8) •Dbf4 (9) •Orc (2) (10) •Cdc45 in vitro (11) •Polymerase alpha in vitro (12)
Sp •Cds1 , Rqh1, Rad21 (13) •Swi6 (hp1) (14) • role in sld3 origin binding (15)
Xl •Mcm3/7 in interphase but not mitotic extracts. (16) •Caf1 (17) • SCC2/4 (18)
Mammals •mcm2 (19) • claspin (20) substrate (21) • importin beta (22) |
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Modifications |
• Autophosphorylation in vitro (23) • Phosphorylated by cds1 in response to HU (13) • Phosphorylated ATR in checkpoint function? (24)
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Structure |
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Cellular location and expression |
Sc •Seen on chromatin all of the cell cycle (23)
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Other comments |
Sc • odd strain dependency (25) • needs orc for recruitment to origins (nb in higher eukaryotes needs mcm but not orc) (26) • suggested role in silencing (27) • suggested role in meiosis (28) (29) (30) (31-33) • required for the full activation of rad53 (34) • role in rDNA segregation (35) Sp • Role in initiating meiotic recombination (36) • suggested rate limiting factor for origin firing (37)
Xl • Some debate about whether needs to act before cdc2 (38) Vs (39) • DNA damage checkpoint works via Cdc7 (24)
Mammals • Often overexpressed in tumour cell lines (40) • Reported splice variants in mouse (41) • Mouse knockouts (42) • Checkpoint role in response to uvc (43) • Suggested role in damage response (44) in es cells (21) • Depletion gives abortive s phase arrest (non transformed cells) and apoptosis (transformed cells) (45) |
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Revised by |
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Last edited |
13 July 09 |
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Dbf4 |
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Synonyms |
SpDfp1, SpHim1, SpRad35 Dm Chiffon (46) Hs ASK An Nimo (47)
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Molecular weight |
81 kDa (Sc) |
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Biochemical properties |
Regulatory subunit of Cdc7 kinase
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Motifs |
Sc •APC destruction boxes (48) (49) (50)
Sp •Zn finger; (51)
Hs •NLS, PEST sequences (52) •2 PEST sequences, BRCT domains (53) 1 involved in response to DNA damage (54) |
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Interactions |
•Cdc7 SC (23) Xl? (52) Sp (55)
Sc •Mcm2 (10) •ORC, Rad53 (56) (57) (58) (9) •Cdc5 (59)
Sp •Swi 1 (60) •Cdc23 (Mcm10) (61)
Mammals •Mcm2 (62)
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Modifications |
Sc •Phosphorylated in S not G2 (23) •Phosphorylated in nocodazole block (50) •Phosphorylated by rad53 (9)
Sp •3 phospho-forms slowest max just before s, disappears at end s . Intermediate peaks g2. •Cds 1 needed for hyperphosphorylation (63) |
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Structure |
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Cellular location and expression |
Sc • Level of Dbf4 varies in cell cycle (Cdc7 level is constant). Low in G1, increases in S phase. •Proteolysis is APC dependent (48) (49) (50)
Mammals • protein levels up in late s /g2 (64) |
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Other comments |
Sc •apc substrate (23)
Sp Spo4/6 Nakamura et al mcb 2002 22 309. Xl •2nd homologue– Drf1 (65) suggest this is the more important for replication while dbf4 involved in meiosis. (66)
Dm • needed for binding of DDK to ORC (67)
Mammals •Related protein that also interacts with cdc7 (68) •often overexpressed in tumour cell lines (40) • ( also Xl) direct positive effect on overcoming DNA damage checkpoint (69) |
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Revised by |
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Last edited |
13 July 09 |
1. Donaldson,A.D., Fangman,W.L. and Brewer,B.J. (1998) Cdc7 is required throughout the yeast S phase to activate replication origins. Genes Dev 12, 491-501.
2. Dowell,S.J., Romanowski,P. and Diffley,J.F. (1994) Interaction of Dbf4, the Cdc7 protein kinase regulatory subunit, with yeast replication origins in vivo. Science 265, 1243-1246.
3. Kakusho,N., Taniyama,C. and Masai,H. (2008) Identification of stimulators and inhibitors of Cdc7 kinase in vitro. J Biol Chem 283, 19211-19218.
4. Kim,B.J., Kim,S.Y. and Lee,H. (2007) Identification and characterization of human cdc7 nuclear retention and export sequences in the context of chromatin binding. J Biol Chem 282, 30029-30038.
5. Kihara,M., Nakai,W., Asano,S., Suzuki,A., Kitada,K., Kawasaki,Y., Johnston,L.H. and Sugino,A. (2000) Characterization of the yeast Cdc7p/Dbf4p complex purified from insect cells. Its protein kinase activity is regulated by Rad53p. J Biol Chem 275, 35051-35062.
6. Sheu,Y.J. and Stillman,B. (2006) Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell 24, 101-113.
7. Masai,H., Taniyama,C., Ogino,K., Matsui,E., Kakusho,N., Matsumoto,S., Kim,J.M., Ishii,A., Tanaka,T., Kobayashi,T., Tamai,K., Ohtani,K. and Arai,K. (2006) Phosphorylation of MCM4 by Cdc7 kinase facilitates its interaction with Cdc45 on the chromatin. J Biol Chem 281, 39249-39261.
8. Hardy,C.F., Dryga,O., Seematter,S., Pahl,P.M. and Sclafani,R.A. (1997) mcm5/cdc46-bob1 bypasses the requirement for the S phase activator Cdc7p. Proc Natl Acad Sci U S A 94, 3151-3155.
9. Kitada,K., Johnson,A.L., Johnston,L.H. and Sugino,A. (1993) A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Mol Cell Biol 13, 4445-4457.
10. Varrin,A.E., Prasad,A.A., Scholz,R.P., Ramer,M.D. and Duncker,B.P. (2005) A mutation in Dbf4 motif M impairs interactions with DNA replication factors and confers increased resistance to genotoxic agents. Mol Cell Biol 25, 7494-7504.
11. Nougarede,R., Della Seta,F., Zarzov,P. and Schwob,E. (2000) Hierarchy of S-phase-promoting factors: yeast Dbf4-Cdc7 kinase requires prior S-phase cyclin-dependent kinase activation. Mol Cell Biol 20, 3795-3806.
12. Pasero,P. and Schwob,E. (2000) Think global, act local--how to regulate S phase from individual replication origins. Curr Opin Genet Dev 10, 178-186.
13. Snaith,H.A., Brown,G.W. and Forsburg,S.L. (2000) Schizosaccharomyces pombe Hsk1p is a potential cds1p target required for genome integrity. Mol Cell Biol20, 7922-7932.
14. Bailis,J.M., Bernard,P., Antonelli,R., Allshire,R.C. and Forsburg,S.L. (2003) Hsk1-Dfp1 is required for heterochromatin-mediated cohesion at centromeres. Nat Cell Biol 5, 1111-1116.
15. Yabuuchi,H., Yamada,Y., Uchida,T., Sunathvanichkul,T., Nakagawa,T. and Masukata,H. (2006) Ordered assembly of Sld3, GINS and Cdc45 is distinctly regulated by DDK and CDK for activation of replication origins. EMBO J 25, 4663-4674.
16. Kneissl,M., Putter,V., Szalay,A.A. and Grummt,F. (2003) Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells. J Mol Biol 327, 111-128.
17. Gerard,A., Koundrioukoff,S., Ramillon,V., Sergere,J.C., Mailand,N., Quivy,J.P. and Almouzni,G. (2006) The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen. EMBO Rep 7, 817-823.
18. Takahashi,T.S., Basu,A., Bermudez,V., Hurwitz,J. and Walter,J.C. (2008) Cdc7-Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts. Genes Dev 22, 1894-1905.
19. Cho,W.H., Lee,Y.J., Kong,S.I., Hurwitz,J. and Lee,J.K. (2006) CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein. Proc Natl Acad Sci U S A 103, 11521-11526.
20. Kim,J.M., Kakusho,N., Yamada,M., Kanoh,Y., Takemoto,N. and Masai,H. (2007) Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene
21. Kim,J.M., Kakusho,N., Yamada,M., Kanoh,Y., Takemoto,N. and Masai,H. (2008) Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene27, 3475-3482.
22. Kim,B.J. and Lee,H. (2006) Importin-beta mediates Cdc7 nuclear import by binding to the kinase insert II domain, which can be antagonized by importin-alpha. J Biol Chem 281, 12041-12049.
23. Weinreich,M. and Stillman,B. (1999) Cdc7p-Dbf4p kinase binds to chromatin during S phase and is regulated by both the APC and the RAD53 checkpoint pathway. EMBO J 18, 5334-5346.
24. Costanzo,V., Shechter,D., Lupardus,P.J., Cimprich,K.A., Gottesman,M. and Gautier,J. (2003) An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell 11, 203-213.
25. Tavormina,P.A., Wang,Y. and Burke,D.J. (1997) Differential requirements for DNA replication in the activation of mitotic checkpoints in Saccharomyces cerevisiae. Mol Cell Biol 17, 3315-3322.
26. Edwards,M.C., Tutter,A.V., Cvetic,C., Gilbert,C.H., Prokhorova,T.A. and Walter,J.C. (2002) MCM2-7 complexes bind chromatin in a distributed pattern surrounding the origin recognition complex in Xenopus egg extracts. J Biol Chem277, 33049-33057.
27. Rehman,M.A., Fourel,G., Mathews,A., Ramdin,D., Espinosa,M., Gilson,E. and Yankulov,K. (2006) Differential requirement of DNA replication factors for subtelomeric ARS consensus sequence protosilencers in Saccharomyces cerevisiae. Genetics174, 1801-1810.
28. Valentin,G., Schwob,E. and Della Seta,F. (2006) Dual role of the Cdc7-regulatory protein Dbf4 during yeast meiosis. J Biol Chem 281, 2828-2834.
29. Wan,L., Zhang,C., Shokat,K.M. and Hollingsworth,N.M. (2006) Chemical inactivation of cdc7 kinase in budding yeast results in a reversible arrest that allows efficient cell synchronization prior to meiotic recombination. Genetics174, 1767-1774.
30. Sasanuma,H., Hirota,K., Fukuda,T., Kakusho,N., Kugou,K., Kawasaki,Y., Shibata,T., Masai,H. and Ohta,K. (2008) Cdc7-dependent phosphorylation of Mer2 facilitates initiation of yeast meiotic recombination. Genes Dev 22, 398-410.
31. Wan,L., Niu,H., Futcher,B., Zhang,C., Shokat,K.M., Boulton,S.J. and Hollingsworth,N.M. (2008) Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes Dev 22, 386-397.
32. Lo,H.C., Wan,L., Rosebrock,A., Futcher,B. and Hollingsworth,N.M. (2008) Cdc7-Dbf4 regulates NDT80 transcription as well as reductional segregation during budding yeast meiosis. Mol Biol Cell 19, 4956-4967.
33. Matos,J., Lipp,J.J., Bogdanova,A., Guillot,S., Okaz,E., Junqueira,M., Shevchenko,A. and Zachariae,W. (2008) Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell 135, 662-678.
34. Ogi,H., Wang,C.Z., Nakai,W., Kawasaki,Y. and Masumoto,H. (2008) The role of the Saccharomyces cerevisiae Cdc7-Dbf4 complex in the replication checkpoint. Gene 414, 32-40.
35. Sullivan,M., Holt,L. and Morgan,D.O. (2008) Cyclin-specific control of ribosomal DNA segregation. Mol Cell Biol 28, 5328-5336.
36. Ogino,K., Hirota,K., Matsumoto,S., Takeda,T., Ohta,K., Arai,K. and Masai,H. (2006) Hsk1 kinase is required for induction of meiotic dsDNA breaks without involving checkpoint kinases in fission yeast. Proc Natl Acad Sci U S A 103, 8131-8136.
37. Patel,P.K., Kommajosyula,N., Rosebrock,A., Bensimon,A., Leatherwood,J., Bechhoefer,J. and Rhind,N. (2008) The Hsk1(Cdc7) replication kinase regulates origin efficiency. Mol Biol Cell 19, 5550-5558.
38. Jares,P. and Blow,J.J. (2000) Xenopus cdc7 function is dependent on licensing but not on XORC, XCdc6, or CDK activity and is required for XCdc45 loading. Genes Dev 14, 1528-1540.
39. Walter,J.C. (2000) Evidence for sequential action of cdc7 and cdk2 protein kinases during initiation of DNA replication in Xenopus egg extracts. J Biol Chem275, 39773-39778.
40. Sclafani,R.A. (2000) Cdc7p-Dbf4p becomes famous in the cell cycle. J Cell Sci 113, 2111-2117.
41. Kim,J.M., Sato,N., Yamada,M., Arai,K. and Masai,H. (1998) Growth regulation of the expression of mouse cDNA and gene encoding a serine/threonine kinase related to Saccharomyces cerevisiae CDC7 essential for G1/S transition. Structure, chromosomal localization, and expression of mouse gene for s. cerevisiae Cdc7-related kinase. J Biol Chem 273, 23248-23257.
42. Kim,J.M., Nakao,K., Nakamura,K., Saito,I., Katsuki,M., Arai,K. and Masai,H. (2002) Inactivation of Cdc7 kinase in mouse ES cells results in S-phase arrest and p53-dependent cell death. EMBO J 21, 2168-2179.
43. Heffernan,T.P., Unsal-Kacmaz,K., Heinloth,A.N., Simpson,D.A., Paules,R.S., Sancar,A., Cordeiro-Stone,M. and Kaufmann,W.K. (2007) Cdc7-Dbf4 and the human S checkpoint response to UVC. J Biol Chem 282, 9458-9468.
44. Tenca,P., Brotherton,D., Montagnoli,A., Rainoldi,S., Albanese,C. and Santocanale,C. (2007) Cdc7 is an active kinase in human cancer cells undergoing replication stress. J Biol Chem 282, 208-215.
45. Im,J.S. and Lee,J.K. (2008) ATR-dependent activation of p38 MAP kinase is responsible for apoptotic cell death in cells depleted of Cdc7. J Biol Chem 283, 25171-25177.
46. Landis,G. and Tower,J. (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 126, 4281-4293.
47. James,S.W., Bullock,K.A., Gygax,S.E., Kraynack,B.A., Matura,R.A., MacLeod,J.A., McNeal,K.K., Prasauckas,K.A., Scacheri,P.C., Shenefiel,H.L., Tobin,H.M. and Wade,S.D. (1999) nimO, an Aspergillus gene related to budding yeast Dbf4, is required for DNA synthesis and mitotic checkpoint control. J Cell Sci 112, 1313-1324.
48. Oshiro,G., Owens,J.C., Shellman,Y., Sclafani,R.A. and Li,J.J. (1999) Cell cycle control of Cdc7p kinase activity through regulation of Dbf4p stability. Mol Cell Biol19, 4888-4896.
49. Cheng,L., Collyer,T. and Hardy,C.F. (1999) Cell cycle regulation of DNA replication initiator factor Dbf4p. Mol Cell Biol 19, 4270-4278.
50. Ferreira,M.F., Santocanale,C., Drury,L.S. and Diffley,J.F. (2000) Dbf4p, an essential S phase-promoting factor, is targeted for degradation by the anaphase-promoting complex. Mol Cell Biol 20, 242-248.
51. Ogino,K., Takeda,T., Matsui,E., Iiyama,H., Taniyama,C., Arai,K. and Masai,H. (2001) Bipartite binding of a kinase activator activates Cdc7-related kinase essential for S phase. J Biol Chem 276, 31376-31387.
52. Kumagai,H., Sato,N., Yamada,M., Mahony,D., Seghezzi,W., Lees,E., Arai,K. and Masai,H. (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. Mol Cell Biol 19, 5083-5095.
53. Jiang,W., McDonald,D., Hope,T.J. and Hunter,T. (1999) Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. EMBO J 18, 5703-5713.
54. Gabrielse,C., Miller,C.T., McConnell,K.H., DeWard,A., Fox,C.A. and Weinreich,M. (2006) A Dbf4p BRCA1 C-terminal-like domain required for the response to replication fork arrest in budding yeast. Genetics 173, 541-555.
55. Brown,G.W. and Kelly,T.J. (1998) Purification of Hsk1, a minichromosome maintenance protein kinase from fission yeast. J Biol Chem 273, 22083-22090.
56. Duncker,B.P., Shimada,K., Tsai-Pflugfelder,M., Pasero,P. and Gasser,S.M. (2002) An N-terminal domain of Dbf4p mediates interaction with both origin recognition complex (ORC) and Rad53p and can deregulate late origin firing. Proc Natl Acad Sci U S A 99, 16087-16092.
57. Dohrmann,P.R., Oshiro,G., Tecklenburg,M. and Sclafani,R.A. (1999) RAD53 regulates DBF4 independently of checkpoint function in Saccharomyces cerevisiae. Genetics 151, 965-977.
58. Hardy,C.F. (1996) Characterization of an essential Orc2p-associated factor that plays a role in DNA replication. Mol Cell Biol 16, 1832-1841.
59. Hardy,C.F. and Pautz,A. (1996) A novel role for Cdc5p in DNA replication. Mol Cell Biol 16, 6775-6782.
60. Matsumoto,S., Ogino,K., Noguchi,E., Russell,P. and Masai,H. (2005) Hsk1-Dfp1/Him1, the Cdc7-Dbf4 kinase in Schizosaccharomyces pombe, associates with Swi1, a component of the replication fork protection complex. J Biol Chem 280, 42536-42542.
61. Lee,J.K., Seo,Y.S. and Hurwitz,J. (2003) The Cdc23 (Mcm10) protein is required for the phosphorylation of minichromosome maintenance complex by the Dfp1-Hsk1 kinase. Proc Natl Acad Sci U S A 100, 2334-2339.
62. Tsuji,T., Ficarro,S.B. and Jiang,W. (2006) Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells. Mol Biol Cell 17, 4459-4472.
63. Brown,G.W. and Kelly,T.J. (1999) Cell cycle regulation of Dfp1, an activator of the Hsk1 protein kinase. Proc Natl Acad Sci U S A 96, 8443-8448.
64. Yoshizawa-Sugata,N., Ishii,A., Taniyama,C., Matsui,E., Arai,K. and Masai,H. (2005) A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases. J Biol Chem 280, 13062-13070.
65. Yanow,S.K., Gold,D.A., Yoo,H.Y. and Dunphy,W.G. (2003) Xenopus Drf1, a regulator of Cdc7, displays checkpoint-dependent accumulation on chromatin during an S-phase arrest. J Biol Chem 278, 41083-41092.
66. Silva,T., Bradley,R.H., Gao,Y. and Coue,M. (2006) Xenopus CDC7/DRF1 complex is required for the initiation of DNA replication. J Biol Chem 281, 11569-11576.
67. Zhang,H. and Tower,J. (2004) Sequence requirements for function of the Drosophila chorion gene locus ACE3 replicator and ori-beta origin elements. Development 131, 2089-2099.
68. Montagnoli,A., Bosotti,R., Villa,F., Rialland,M., Brotherton,D., Mercurio,C., Berthelsen,J. and Santocanale,C. (2002) Drf1, a novel regulatory subunit for human Cdc7 kinase. EMBO J 21, 3171-3181.
69. Tsuji,T., Lau,E., Chiang,G.G. and Jiang,W. (2008) The role of Dbf4/Drf1-dependent kinase Cdc7 in DNA-damage checkpoint control. Mol Cell 32, 862-869.