Required for initiation and elongation steps of DNA replication. May be part of Mcm2-7 helicase complex with GINS. Required after preRC step for loading of various proteins for initiation and elongation (1) eg pol alpha (2)




Sld4; SpSna41

Molecular weight

74 kDa (Sc); 63kDa xenopus (2)


Biochemical properties



NLS (3)

Protein interactions


• mcm2,3.and 5 as part of big complex. (4) , some dependence on  cdc7 phosphorylation (5)

•pole (6)

•rpa70 (6) (co-dependency for ori binding /interaction needs cdk activity).

•Dbp11 (7) (genetic) (for polymerase switching?)

•Sld3 (8) (genetic)

•GINS and MCMs as complex (9)



 •Pol alpha (10)



•GINS and MCM complexes (as part of helicase at fork) (11) .



•GINS and MCM complexes (as part of helicase). (12)



•Orc2 - (13)

•Pola (14)

•pol delta and epsilon but not alpha/PCNA suggest cdc45/polepsilon complex interacts mcm7 (15)

•topbp1 (16)




•ubiquitylated for degradation (17)



Cellular location and expression


•Binds to pre-RC before CDK/DDK activation in low affinity mode, but more tightly after CDK/DDK activation (18) ( {Kanemaki 19) . Part of replication fork complex and required for elongation step of DNA replication (1) (9)

• nuclear throughout cell cycle (20) ,

•chromatin binding g1/s to late s/g2) (4)



•Binds to initiation in sequence that depends on first Sld3, then GINS and Cut5. DDK and CDK required for Cdc45 chromatin association (21)



• localises to sites of chorion amplification (22)



•nuclear g1/s till late s, then leaves nucleus (13)



Other comments


• suggested effect on silencing (23)



•Chromatin association inhibited by PP2A (24)



•several isoforms (14)

•causes massive decondensation of chromatin when targeted to a region by lac. Partly suppressed p21 (25)

•mouse knockout lethal (26)

•overexpressed tumour cells (27)

• checkpoint target (28)


Revised by


Last edited

13 April 08



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2.    Mimura,S. and Takisawa,H. (1998) Xenopus Cdc45-dependent loading of DNA polymerase alpha onto chromatin under the control of S-phase Cdk. EMBO J 17, 5699-5707.

3.    Hopwood,B. and Dalton,S. (1996) Cdc45p assembles into a complex with Cdc46p/Mcm5p, is required for minichromosome maintenance, and is essential for chromosomal DNA replication. Proc Natl Acad Sci U S A 93, 12309-12314.

4.    Zou,L. and Stillman,B. (1998) Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin. Science 280, 593-596.

5.    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.

6.    Zou,L. and Stillman,B. (2000) Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase. Mol Cell Biol 20, 3086-3096.

7.    Reid,R.J., Fiorani,P., Sugawara,M. and Bjornsti,M.A. (1999) CDC45 and DPB11 are required for processive DNA replication and resistance to DNA topoisomerase I-mediated DNA damage. Proc Natl Acad Sci U S A 96, 11440-11445.

8.    Kamimura,Y., Tak,Y.S., Sugino,A. and Araki,H. (2001) Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae. EMBO J 20, 2097-2107.

9.    Gambus,A., Jones,R.C., Sanchez-Diaz,A., Kanemaki,M., van Deursen,F., Edmondson,R.D. and Labib,K. (2006) GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol 8, 358-366.

10.  Uchiyama,M., Griffiths,D., Arai,K. and Masai,H. (2001) Essential role of Sna41/Cdc45 in loading of DNA polymerase alpha onto minichromosome maintenance proteins in fission yeast. J Biol Chem 276, 26189-26196.

11.  Pacek,M., Tutter,A.V., Kubota,Y., Takisawa,H. and Walter,J.C. (2006) Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol Cell 21, 581-587.

12.  Moyer,S.E., Lewis,P.W. and Botchan,M.R. (2006) Isolation of the Cdc45/Mcm2-7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase. Proc Natl Acad Sci U S A 103, 10236-10241.

13.  Saha,P., Thome,K.C., Yamaguchi,R., Hou,Z., Weremowicz,S. and Dutta,A. (1998) The human homolog of Saccharomyces cerevisiae CDC45. J Biol Chem 273, 18205-18209.

14.  Kukimoto,I., Igaki,H. and Kanda,T. (1999) Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha. Eur J Biochem 265, 936-943.

15.  Bauerschmidt,C., Pollok,S., Kremmer,E., Nasheuer,H.P. and Grosse,F. (2007) Interactions of human Cdc45 with the Mcm2-7 complex, the GINS complex, and DNA polymerases delta and epsilon during S phase. Genes Cells 12, 745-758.

16.  Schmidt,U., Wollmann,Y., Franke,C., Grosse,F., Saluz,H.P. and Hanel,F. (2008) Characterization of the interaction between the human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein. Biochem J 409, 169-177.

17.  Pollok,S. and Grosse,F. (2007) Cdc45 degradation during differentiation and apoptosis. Biochem Biophys Res Commun 362, 910-915.

18.  Aparicio,O.M., Weinstein,D.M. and Bell,S.P. (1997) Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase. Cell 91, 59-69.

19.  Kanemaki,M. and Labib,K. (2006) Distinct roles for Sld3 and GINS during establishment and progression of eukaryotic DNA replication forks. EMBO J 25, 1753-1763.

20.  Owens,J.C., Detweiler,C.S. and Li,J.J. (1997) CDC45 is required in conjunction with CDC7/DBF4 to trigger the initiation of DNA replication. Proc Natl Acad Sci U S A 94, 12521-12526.

21.  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.

22.  Loebel,D., Huikeshoven,H. and Cotterill,S. (2000) Localisation of the DmCdc45 DNA replication factor in the mitotic cycle and during chorion gene amplification. Nucleic Acids Res 28, 3897-3903.

23.  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.

24.  Petersen,P., Chou,D.M., You,Z., Hunter,T., Walter,J.C. and Walter,G. (2006) Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint. Mol Cell Biol 26, 1997-2011.

25.  Alexandrow,M.G. and Hamlin,J.L. (2005) Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation. J Cell Biol 168, 875-886.

26.  Yoshida,K., Kuo,F., George,E.L., Sharpe,A.H. and Dutta,A. (2001) Requirement of CDC45 for postimplantation mouse development. Mol Cell Biol 21, 4598-4603.

27.  Pollok,S., Bauerschmidt,C., Sanger,J., Nasheuer,H.P. and Grosse,F. (2007) Human Cdc45 is a proliferation-associated antigen. FEBS J 274, 3669-3684.

28.  Liu,P., Barkley,L.R., Day,T., Bi,X., Slater,D.M., Alexandrow,M.G., Nasheuer,H.P. and Vaziri,C. (2006) The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem281, 30631-30644.