Mcm10
Required for initiation and elongation stages of DNA replication. Implicated in chromatin binding of Cdc45 and DNA pol alpha. Also required for stability of DNA pol alpha catalytic subunit in S. cerevisiae.
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Synonyms |
ScDna43; SpCdc23 |
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Molecular weight |
66 kDa (Sc) 117 kDa (Hs) plus some at 125 and 135 |
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Biochemical properties |
•DNA binding ss NTPase activity (1) •Primase activity (2) ( not Xl - (3) |
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Motifs |
Sc •Zn finger (4) conserved in other organisms eg Sp (1) •NLS •PIP box (5) • hsp10 like domain (6) conserved mammals (7) |
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Protein interactions |
Sc •Orc (8) •dpb11 dpb2 cdc45 mcm3/7 DNA2 mms22 mms1 (synthetic lethal) (9) •Cdc45 (10) ( not Xl) (3) •Sir2/3 (11) •Pol alpha – 50% mcm10 associated at all phases of the cell cycle (12) ?? •PCNA (5) •Mcm2-7 (13)
Sp •Cdc24 (14) (genetic) •Pola (stimulates activity) (2) •Mcm2-7, ORC (15) • ABP1 (cenp-b homologue) (16)
Mammals •Mcm2/6 (2 hybrid screen (17) • polymerase alpha (7) (18) •AND1 (18)
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Modifications |
• Ub (19) (5) conserved between yeast and mammals
Mammals •Phosphorylation (hyper g2/m) (19) |
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Structure |
Sc • DNA binding architecture (20)
Xl • domain structure (20)
Mammals • ring shaped hexamer • crystal structure of zinc binding domain (21) |
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Cellular location and expression |
Sc •appears to bind to chromatin after pre-RC formation, ie requires Mcm2-7 for chromatin binding. (12) •level doesn’t vary much in the cell cycle. (8) •bound to chromatin throughout the cell cycle. (8) •binding needs mcm2-7 and moves with the replication fork (12)
Xl •appears to bind to chromatin after pre-RC formation, ie requires Mcm2-7 for chromatin binding. (22)
Dm
Mammals • nuclear in g1 and s. dissociation in g2 (17) • chromatin loading pattern like pcna (19) • doesn’t colocalise BrdU (19)
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Other comments |
Sc • 40-60x more abundant than orc (8) • self associates into large complexes > 800kDa in vitro (4) • needed for cdc45 chromatin binding (10) • needed for DNA pol alpha chromatin association also needed to stabilise DNApol alpha catalytic subunit, same abundance as other mcms. (12)
Sp •Required for Cdc45 chromatin binding (23) •Functionally conserved between Sc and Sp (24)
Xl • Required for Cdc45 chromatin binding. 2 molecules per origin loaded (22) • not required for mcm loading
Dm •Functionally conserved between Sc and Dm (25)
Mammals • 5-10 copies per origin (26) • e2f sites in promoter (27)
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Revised by |
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Last edited |
14 July 09 |
1. Fien,K., Cho,Y.S., Lee,J.K., Raychaudhuri,S., Tappin,I. and Hurwitz,J. (2004) Primer utilization by DNA polymerase alpha-primase is influenced by its interaction with Mcm10p. J Biol Chem279, 16144-16153.
2. Fien,K. and Hurwitz,J. (2006) Fission yeast Mcm10p contains primase activity. J Biol Chem 281, 22248-22260.
3. Robertson,P.D., Warren,E.M., Zhang,H., Friedman,D.B., Lary,J.W., Cole,J.L., Tutter,A.V., Walter,J.C., Fanning,E. and Eichman,B.F. (2008) Domain architecture and biochemical characterization of vertebrate Mcm10. J Biol Chem 283, 3338-3348.
4. Cook,C.R., Kung,G., Peterson,F.C., Volkman,B.F. and Lei,M. (2003) A novel zinc finger is required for Mcm10 homocomplex assembly. J Biol Chem278, 36051-36058.
5. Das-Bradoo,S., Ricke,R.M. and Bielinsky,A.K. (2006) Interaction between PCNA and diubiquitinated Mcm10 is essential for cell growth in budding yeast. Mol Cell Biol 26, 4806-4817.
6. Ricke,R.M. and Bielinsky,A.K. (2006) A conserved Hsp10-like domain in Mcm10 is required to stabilize the catalytic subunit of DNA polymerase-alpha in budding yeast. J Biol Chem 281, 18414-18425.
7. Chattopadhyay,S. and Bielinsky,A.K. (2007) Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication. Mol Biol Cell 18, 4085-4095.
8. Kawasaki,Y., Hiraga,S. and Sugino,A. (2000) Interactions between Mcm10p and other replication factors are required for proper initiation and elongation of chromosomal DNA replication in Saccharomyces cerevisiae. Genes Cells 5, 975-989.
9. Araki,Y., Kawasaki,Y., Sasanuma,H., Tye,B.K. and Sugino,A. (2003) Budding yeast mcm10/dna43 mutant requires a novel repair pathway for viability. Genes Cells 8, 465-480.
10. Sawyer,S.L., Cheng,I.H., Chai,W. and Tye,B.K. (2004) Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiae. J Mol Biol 340, 195-202.
11. Liachko,I. and Tye,B.K. (2005) Mcm10 is required for the maintenance of transcriptional silencing in Saccharomyces cerevisiae. Genetics 171, 503-515.
12. Ricke,R.M. and Bielinsky,A.K. (2004) Mcm10 regulates the stability and chromatin association of DNA polymerase-alpha. Mol Cell 16, 173-185.
13. Homesley,L., Lei,M., Kawasaki,Y., Sawyer,S., Christensen,T. and Tye,B.K. (2000) Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins. Genes Dev 14, 913-926.
14. Tanaka,H., Tanaka,K., Murakami,H. and Okayama,H. (1999) Fission yeast cdc24 is a replication factor C- and proliferating cell nuclear antigen-interacting factor essential for S-phase completion. Mol Cell Biol 19, 1038-1048.
15. Hart,E.A., Bryant,J.A., Moore,K. and Aves,S.J. (2002) Fission yeast Cdc23 interactions with DNA replication initiation proteins. Curr Genet 41, 342-348.
16. Locovei,A.M., Spiga,M.G., Tanaka,K., Murakami,Y. and D'Urso,G. (2006) The CENP-B homolog, Abp1, interacts with the initiation protein Cdc23 (MCM10) and is required for efficient DNA replication in fission yeast. Cell Div 1, 27.
17. Izumi,M., Yanagi,K., Mizuno,T., Yokoi,M., Kawasaki,Y., Moon,K.Y., Hurwitz,J., Yatagai,F. and Hanaoka,F. (2000) The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase. Nucleic Acids Res 28, 4769-4777.
18. Zhu,W., Ukomadu,C., Jha,S., Senga,T., Dhar,S.K., Wohlschlegel,J.A., Nutt,L.K., Kornbluth,S. and Dutta,A. (2007) Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication. Genes Dev21, 2288-2299.
19. Izumi,M., Yatagai,F. and Hanaoka,F. (2001) Cell cycle-dependent proteolysis and phosphorylation of human Mcm10. J Biol Chem 276, 48526-48531.
20. Warren,E.M., Vaithiyalingam,S., Haworth,J., Greer,B., Bielinsky,A.K., Chazin,W.J. and Eichman,B.F. (2008) Structural basis for DNA binding by replication initiator Mcm10. Structure 16, 1892-1901.
21. Jung,N.Y., Bae,W.J., Chang,J.H., Kim,Y.C. and Cho,Y. (2008) Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of the central zinc-binding domain of the human Mcm10 DNA-replication factor. Acta Crystallogr Sect F Struct Biol Cryst Commun 64, 495-497.
22. Wohlschlegel,J.A., Dhar,S.K., Prokhorova,T.A., Dutta,A. and Walter,J.C. (2002) Xenopus Mcm10 binds to origins of DNA replication after Mcm2-7 and stimulates origin binding of Cdc45. Mol Cell 9, 233-240.
23. Gregan,J., Lindner,K., Brimage,L., Franklin,R., Namdar,M., Hart,E.A., Aves,S.J. and Kearsey,S.E. (2003) Fission yeast Cdc23/Mcm10 functions after pre-replicative complex formation to promote Cdc45 chromatin binding. Mol Biol Cell14, 3876-3887.
24. Aves,S.J., Tongue,N., Foster,A.J. and Hart,E.A. (1998) The essential schizosaccharomyces pombe cdc23 DNA replication gene shares structural and functional homology with the Saccharomyces cerevisiae DNA43 (MCM10) gene. Curr Genet34, 164-171.
25. Christensen,T.W. and Tye,B.K. (2003) Drosophila MCM10 interacts with members of the prereplication complex and is required for proper chromosome condensation. Mol Biol Cell 14, 2206-2215.
26. Izumi,M., Yatagai,F. and Hanaoka,F. (2004) Localization of human Mcm10 is spatially and temporally regulated during the S phase. J Biol Chem 279, 32569-32577.
27. Yoshida,K. and Inoue,I. (2004) Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor. Oncogene 23, 6250-6260.