Mcm2-7

Assembled onto chromatin at ORC to form ‘pre-replicative complex’. On replication initiation, Mcm2-7 moves away from ORC with replication fork. Probably provides helicase activity at fork, possibly in conjunction with other proteins such as GINS and Cdc45. Displaced from chromatin during S phase, probably on replication termination. (1) (2) (3) (4) (5)

Hexameric complex composed of Mcm2, Mcm3, Mcm4, Mcm5, Mcm6 & Mcm7. Note not related to Mcm1 or Mcm10.

Orthologues	RLF-M (Xl)
Molecular weight	Mw 2- 114 (112 phosphorylated), 3 - 100, 4- 98, 5- 92, 6- 102, 7- 90 (6)
Biochemical properties	•3’>5’ helicase activity in vitro (Mcm467) (7) (8) (9) (10) Mcm2,3,5 inhibit helicase activity •DNA binding – ss ATP dependent (10) •ATPase (11) (12) Sc • analysis of properties subcomplexes (13) • properties of mcm4/6/7 vs mcm2-7. suggest phosphorylations serve as switch between open (loading) and closed (helicase) complex. (14) • comparison 4 7 helicase and 4 6 7 helicase activities (15) Dm •May function as helicase in complex with GINS and Cdc45 (16) Mammalian •Human preferential binding to T rich ssDNA (17) but can overlap ds (18) Archaea •Methanobacterium thermoautotrophicum -ATPase stimulated by ds but not ss DNA (19) •Thermoplasma acidophilum helicase stimulated by cdc6 (20) •Thermos aquaticus mcms can’t pass stalled transcription complexes (21) . •analysis Sulfolobus solfataricus mcm - DNA binding (22) ATPase/helicase (23)
Motifs	AAA+ ATPase (24) Archaea • domain mapping (25) (26)
Interactions	Mcm2-7 subunit interactions •Subcomplexes – 4/6/7, 3/5, 2 •Hexamer/Dodecamer in methanobacterium thermoautotrophicum (19) (27) (28) - reported as 7 membered ring (29) Sc- Genetic - (30) (31) Direct - (11) (12) (32) Sp (33) (10) Xl- (34) (6) (35) (36) Mammals- (37) (38) (39) (40) (41) (42) (On chromatin) (43) (44) Dm- (45) Archae (46) Interactions with other proteins Sc •Cdc7-Dbf4 (47) (48) •Cdt1 (49) •Cdc6 (50) •GINS (51) •Csm1 (spo86) (52) •Tof1/Csm3/Mrc1 (53) •Hbo1 (54) • cdc45 (55) Sp •cdc23 (mcm10) (56) genetic •orc 1 2 5 6 (56) genetic •rum 1 (57) – genetic • cds1 (58) •rhp1/rad22 (in hu) (58) Dm •GINS (16) Xl •Cdt1 (59) •tfIIb,e,f,h, and tbp (60) •Rb (61) •Cdc45 (62) • elys/mel (63) Mammals •Cdt1 (64) (65) (66) •RNA polII - (67) (68) •Plk (69) (70) • histones (4/6/7 complex) (71) •suc beads - (72) • SMC1 (73) • FACT (74) •Rad51/Rad52 (75) •AKAP95 (76) •RPA (40) (77) •p27Kip1 • MCM binding protein (with MCM3-7) (78) • int6 ( MCM7 role in removal from chromatin?) (79) • cleavage products of Importin alpha during apoptosis (80) Plants • ETG1 ( E2F target gene 1) (81) Archaea •Gins (82) other • flu virus RNA dependent RNA polymerase (83)
Modifications	Sc • in vitro 2 4 6 phosphorylated by cdc7. (55) . Role for MCM4 phosphorylation in MCM transport (84) Mammals • cdc7 phosphorylation sites (85)
Structure	Mammals •em studies on structure (41) Archae •ring structure ssDNA through the middle and the complementary strand around the outside to keep them apart. (86) • Thermoplasma acidophilum . hexamers in solution (20) • Crystal structure of sulfolobus solfaticus MCM n terminal domain. (87) • Cryo-electron microscopy (88) • central channel is beta hairpin domains (89) • nearly full length Methanothermobacter thermautotrophicus (90)
Cellular location and expression	Sc •Nuclear localization changes during cell cycle (nuclear in late M/G1 (91) (92) Sp •Nuclear throughout cell cycle eg (93) •subunits appear to bind to chromatin simultaneously (94) . •Nuclear localisation depends on Crm1, subunits need to interact for import (95) Dm • some co-dependence of subunit levels (96) Xl •Mcm proteins only bound to chromatin late M-S phase. Some suggestion that don’t all load onto chromatin at the same time (97) Mammals • load in telophase and early G1 (98) • 2 populations 1 bound tightly to chromatin and one not (99)
Other comments	• Big excess compared to origins (eg yeast (100) , Xl (101) ) • xenopus extracts and Drosophila cells can reduce under normal conditions without visible effect replication (102) , (96) . In xenopus suggested role for excess in recovery from replicative stress (103) also for human (104) • Models for helicase : – pumping at a distance (105) . - modified wedge model (106) - Ploughshare model (107) •Possible transcriptional role eg SC (108) mammals (109) •Often overexpressed in transformed cells eg (110) Sp • may be regulated by MRC1 (111) Mammals • hela cells – only mcm2 and 3 can be reduced without affecting proliferation. long term these stop G2 via replication checkpoint and get activation chk1 2 and increased ss and ds DNA damage. origin firing normal but can’t be increased when add chk1 inhibitor as get for wild type cells. Increased sensitivity aphidicolin and HU. (112) Archae •some have 4 mcms some 1mcm, most similar to mcm4? (113) • genome wide mapping of MCM binding sites (114) • Methanothermobacter thermautotrophicus - the loop connecting the n and the c termini is involved in communication between the termini. (115) • thermoplasma acidophilum mcm and cdc6 - stimulates mcm helicase (116)
Revised by
Last edited	9 July 09

Mcm2

Orthologues	Spnda1/Spcdc19 BM28
Molecular weight
Biochemical properties	• activities of mcm2 fragments (117)
Motifs	• ATPase • Nls SC (95) human (118) • Zn finger (xenopus) (6) • N-terminus alternating repeats of basic and acidic (6)
Protein interactions	Sc • Hat1 (119) (mass screen) • Cdc7 (62) • Cdc6 (64) • Hbo1 (54) Mammals •PolII (68)
Modifications	Phosphorylation (CDK, Cdc7, ATR, ATM) (120) Sc •Phosphorylation sites for CDK, Cdc7, ATR related , ATM related (121) (55) •Phosphorylated by ATR/ATM (122) •Phosphorylation increases g1 to M (123) Xenopus •Phosphorylation by ATM/ATR (124) in response to genotoxic stress •Phosphorylated after mitotic exit in cdk independent manner (72) Mammals • G2/M hyperphosphorylation. Good substrate cdc2/cyclinb in vitro (125) • Cdc7 phosphorylation g1/s. Increases ATPase of MCM2-7 complex (120) – may depend on prior phosphorylation by others (126)
Structure
Cellular location and expression
Other comments	Mammals • cleaved in senescence (85) (127)
Revised by
Last edited	9 July 09

Mcm3

Orthologues	Hs P1
Molecular weight
Biochemical properties
Motifs	•ATPase •nls (human) (118) •nes (human) (118) • Zn finger required for activity (128) although suggested not needed in xenopus (6) • n terminus alternating repeats of basic and acidic amino acids (6) •human MCM3 has 4 cdk sites, most phosphorylated in mitosis. (129)
Interactions	Mammals • Map80/ganp (130) (131) • Histone H3 (132) • MCM3AP (133)
Modifications	Sc •Phosphorylation increases g1 to M (123) •Ub (rescue by uba1 mutant (134) Xenopus •Phosphorylation (135) Mammals •Phosphorylation (72) •ATR/ATM (substrate) (122) identification sites of phosphorylation (136) • Acetylation (133) mcm3ap splice variant ganp
Structure
Cellular location and expression
Other comments	Mammals •Protein turnover high although actual level stays the same (137) • Cleaved by caspase 3 in apoptosis (138)
Revised by
Last edited	9 July 09

Mcm4

Orthologues	SpCdc21; Dm dpa
Molecular weight
Biochemical properties
Motifs	• ATPase • Zn finger (6) •N terminus alternating repeats of basic and acidic (6) • pombe c terminal domain mcm4 involved in tolerating low levels dNTPs (139)
Interactions	Sc •Spt16/Pob3 (51) •Mcm10 (140) (51) • cdc7 (141) Mammals •Rb (142)
Modifications	Phosphorylation (CDK, ATR) (143) Sc • mapping cdk sites (55) , possible role in transport (84) • N terminus has 5 conserved cdk sites close to cdc7 sites. Not phosphorylated if cdc7 acts first (144) Xenopus • Phosphorylation twice s then up again in M (cdk) (145) •Phosphorylated has lower affinity for chromatin (146) Mammals • cdk2 dependent in interphase and cdk1 dependent g2/m sites mapped (147) •hyperphosphorylated uv /hu ATR cdk involved in HU (143) (148) •As xenopus (125) •2 step (72) • phosphorylated during EB virus replication (149)
Structure
Cellular location and expression
Other comments	Mammals • have isolated point mutations where homozygous prone to tumours but males not (150)
Revised by
Last edited	9 July 09

Mcm5

Orthologues	ScCdc46; SpNda4
Molecular weight
Biochemical properties
Motifs	•ATPase •n terminus alternating repeats of basic and acidic (6)
Interactions	Sc •Cdc45 (57) – genetic •ddk ( genetic- bob mutant), proposed mechanisms for bypass (151) Mammals • Stat 1 (152) (153) (154) • cyclin E (role in centrisome duplication) (155)
Modifications
Structure
Cellular location and expression
Other comments	Dm • null mutant can endoreplicate (156) . • suggested role in chromatid cohesion (156) c.elegans • needed for post embryonic development (157)
Revised by
Last edited	9 July 09

Mcm6

Orthologues	SpMis5
Molecular weight
Biochemical properties
Motifs	•ATPase •Zn finger (6) •n terminus alternating repeats of basic and acidic (6)
Interactions	Sc •Rpn and vma1 (119) (mass screen) •Smc1 (73)
Modifications	Mammals •Phosphorylation (72)
Structure
Cellular location and expression	Sp • genome wide mcm6 binding (158)
Other comments
Revised by
Last edited	9 July 09

Mcm7

Orthologues	ScCdc47
Molecular weight
Biochemical properties
Motifs	•ATPase •Zn finger (6) •n terminus alternating repeats of basic and acidic (6)
Interactions	Sc •Mcm10 (140) (51) Sp • rad4,chk1 and cds1 synthetically lethal (159) Mammals •Rb N terminus - (160) • mat (161) •Rad17 (162) •P27kip (77) •ATRIP (122) •E6 (163) •Smc1 (73) •Plk1 (69) • BER complex (164)
Modifications	Ubiquitylation (E3-ubiquitin ligase/E6-AP) (165) , also via int6 (79)
Structure
Cellular location and expression
Other comments	Mammals •links to tumour formation (166) (167) (168) (169) (170) (171) (172) (173) • Expression controlled by e2f1-4 (174) • suggested to be involved in feedback on replication (160)
Revised by
Last edited	9 July 09

1. Tanaka,T. and Nasmyth,K. (1998) Association of RPA with chromosomal replication origins requires an Mcm protein, and is regulated by Rad53, and cyclin- and Dbf4-dependent kinases. EMBO J 17, 5182-5191.

2. Labib,K., Tercero,J.A. and Diffley,J.F. (2000) Uninterrupted MCM2-7 function required for DNA replication fork progression. Science 288, 1643-1647.

3. Labib,K., Kearsey,S.E. and Diffley,J.F. (2001) MCM2-7 proteins are essential components of prereplicative complexes that accumulate cooperatively in the nucleus during G1-phase and are required to establish, but not maintain, the S-phase checkpoint. Mol Biol Cell 12, 3658-3667.

4. 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.

5. Aparicio,O.M., Stout,A.M. and Bell,S.P. (1999) Differential assembly of Cdc45p and DNA polymerases at early and late origins of DNA replication. Proc Natl Acad Sci U S A 96, 9130-9135.

6. Kubota,Y., Mimura,S., Nishimoto,S., Masuda,T., Nojima,H. and Takisawa,H. (1997) Licensing of DNA replication by a multi-protein complex of MCM/P1 proteins in Xenopus eggs. EMBO J 16, 3320-3331.

7. Ishimi,Y. (1997) A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem 272, 24508-24513.

8. You,Z., Komamura,Y. and Ishimi,Y. (1999) Biochemical analysis of the intrinsic Mcm4-Mcm6-mcm7 DNA helicase activity. Mol Cell Biol 19, 8003-8015.

9. Sato,M., Gotow,T., You,Z., Komamura-Kohno,Y., Uchiyama,Y., Yabuta,N., Nojima,H. and Ishimi,Y. (2000) Electron microscopic observation and single-stranded DNA binding activity of the Mcm4,6,7 complex. J Mol Biol 300, 421-431.

10. Lee,J.K. and Hurwitz,J. (2000) Isolation and characterization of various complexes of the minichromosome maintenance proteins of Schizosaccharomyces pombe. J Biol Chem 275, 18871-18878.

11. Schwacha,A. and Bell,S.P. (2001) Interactions between two catalytically distinct MCM subgroups are essential for coordinated ATP hydrolysis and DNA replication. Mol Cell 8, 1093-1104.

12. Davey,M.J., Indiani,C. and O'Donnell,M. (2003) Reconstitution of the Mcm2-7p heterohexamer, subunit arrangement, and ATP site architecture. J Biol Chem 278, 4491-4499.

13. Bochman,M.L. and Schwacha,A. (2007) Differences in the single-stranded DNA binding activities of MCM2-7 and MCM467: MCM2 and MCM5 define a slow ATP-dependent step. J Biol Chem 282, 33795-33804.

14. Bochman,M.L. and Schwacha,A. (2008) The Mcm2-7 complex has in vitro helicase activity. Mol Cell 31, 287-293.

15. Kanter,D.M., Bruck,I. and Kaplan,D.L. (2008) Mcm subunits can assemble into two different active unwinding complexes. J Biol Chem 283, 31172-31182.

16. 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.

17. You,Z., Ishimi,Y., Mizuno,T., Sugasawa,K., Hanaoka,F. and Masai,H. (2003) Thymine-rich single-stranded DNA activates Mcm4/6/7 helicase on Y-fork and bubble-like substrates. EMBO J 22, 6148-6160.

18. You,Z. and Masai,H. (2005) DNA binding and helicase actions of mouse MCM4/6/7 helicase. Nucleic Acids Res 33, 3033-3047.

19. Chong,J.P., Hayashi,M.K., Simon,M.N., Xu,R.M. and Stillman,B. (2000) A double-hexamer archaeal minichromosome maintenance protein is an ATP-dependent DNA helicase. Proc Natl Acad Sci U S A 97, 1530-1535.

20. Haugland,G.T., Shin,J.H., Birkeland,N.K. and Kelman,Z. (2006) Stimulation of MCM helicase activity by a Cdc6 protein in the archaeon Thermoplasma acidophilum. Nucleic Acids Res 34, 6337-6344.

21. Shin,J.H., Santangelo,T.J., Xie,Y., Reeve,J.N. and Kelman,Z. (2007) Archaeal minichromosome maintenance (MCM) helicase can unwind DNA bound by archaeal histones and transcription factors. J Biol Chem 282, 4908-4915.

22. Rothenberg,E., Trakselis,M.A., Bell,S.D. and Ha,T. (2007) MCM forked substrate specificity involves dynamic interaction with the 5'-tail. J Biol Chem 282, 34229-34234.

23. Moreau,M.J., McGeoch,A.T., Lowe,A.R., Itzhaki,L.S. and Bell,S.D. (2007) ATPase site architecture and helicase mechanism of an archaeal MCM. Mol Cell 28, 304-314.

24. Koonin,E.V. (1993) A common set of conserved motifs in a vast variety of putative nucleic acid-dependent ATPases including MCM proteins involved in the initiation of eukaryotic DNA replication. Nucleic Acids Res 21, 2541-2547.

25. Barry,E.R., McGeoch,A.T., Kelman,Z. and Bell,S.D. (2007) Archaeal MCM has separable processivity, substrate choice and helicase domains. Nucleic Acids Res 35, 988-998.

26. Pucci,B., De Felice,M., Rocco,M., Esposito,F., De Falco,M., Esposito,L., Rossi,M. and Pisani,F.M. (2007) Modular organization of the Sulfolobus solfataricus mini-chromosome maintenance protein. J Biol Chem 282, 12574-12582.

27. Kelman,Z., Lee,J.K. and Hurwitz,J. (1999) The single minichromosome maintenance protein of Methanobacterium thermoautotrophicum DeltaH contains DNA helicase activity. Proc Natl Acad Sci U S A 96, 14783-14788.

28. Gomez-Llorente,Y., Fletcher,R.J., Chen,X.S., Carazo,J.M. and San Martin,C. (2005) Polymorphism and double hexamer structure in the archaeal minichromosome maintenance (MCM) helicase from Methanobacterium thermoautotrophicum. J Biol Chem 280, 40909-40915.

29. Yu,X., VanLoock,M.S., Poplawski,A., Kelman,Z., Xiang,T., Tye,B.K. and Egelman,E.H. (2002) The Methanobacterium thermoautotrophicum MCM protein can form heptameric rings. EMBO Rep 3, 792-797.

30. Lei,M., Kawasaki,Y. and Tye,B.K. (1996) Physical interactions among Mcm proteins and effects of Mcm dosage on DNA replication in Saccharomyces cerevisiae. Mol Cell Biol 16, 5081-5090.

31. Dalton,S. and Hopwood,B. (1997) Characterization of Cdc47p-minichromosome maintenance complexes in Saccharomyces cerevisiae: identification of Cdc45p as a subunit. Mol Cell Biol 17, 5867-5875.

32. Bochman,M.L., Bell,S.P. and Schwacha,A. (2008) Subunit organization of Mcm2-7 and the unequal role of active sites in ATP hydrolysis and viability. Mol Cell Biol 28, 5865-5873.

33. Sherman,D.A., Pasion,S.G. and Forsburg,S.L. (1998) Multiple domains of fission yeast Cdc19p (MCM2) are required for its association with the core MCM complex. Mol Biol Cell 9, 1833-1845.

34. Romanowski,P., Madine,M.A. and Laskey,R.A. (1996) XMCM7, a novel member of the Xenopus MCM family, interacts with XMCM3 and colocalizes with it throughout replication. Proc Natl Acad Sci U S A 93, 10189-10194.

35. Thommes,P., Kubota,Y., Takisawa,H. and Blow,J.J. (1997) The RLF-M component of the replication licensing system forms complexes containing all six MCM/P1 polypeptides. EMBO J 16, 3312-3319.

36. Prokhorova,T.A. and Blow,J.J. (2000) Sequential MCM/P1 subcomplex assembly is required to form a heterohexamer with replication licensing activity. J Biol Chem 275, 2491-2498.

37. Burkhart,R., Schulte,D., Hu,D., Musahl,C., Gohring,F. and Knippers,R. (1995) Interactions of human nuclear proteins P1Mcm3 and P1Cdc46. Eur J Biochem 228, 431-438.

38. Musahl,C., Schulte,D., Burkhart,R. and Knippers,R. (1995) A human homologue of the yeast replication protein Cdc21. Interactions with other Mcm proteins. Eur J Biochem 230, 1096-1101.

39. Alexandrow,M.G., Ritzi,M., Pemov,A. and Hamlin,J.L. (2002) A potential role for mini-chromosome maintenance (MCM) proteins in initiation at the dihydrofolate reductase replication origin. J Biol Chem 277, 2702-2708.

40. 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.

41. Yabuta,N., Kajimura,N., Mayanagi,K., Sato,M., Gotow,T., Uchiyama,Y., Ishimi,Y. and Nojima,H. (2003) Mammalian Mcm2/4/6/7 complex forms a toroidal structure. Genes Cells 8, 413-421.

42. Yu,Z., Feng,D. and Liang,C. (2004) Pairwise interactions of the six human MCM protein subunits. J Mol Biol 340, 1197-1206.

43. Ritzi,M., Baack,M., Musahl,C., Romanowski,P., Laskey,R.A. and Knippers,R. (1998) Human minichromosome maintenance proteins and human origin recognition complex 2 protein on chromatin. J Biol Chem 273, 24543-24549.

44. Schaarschmidt,D., Ladenburger,E.M., Keller,C. and Knippers,R. (2002) Human Mcm proteins at a replication origin during the G1 to S phase transition. Nucleic Acids Res 30, 4176-4185.

45. Crevel,G., Ivetic,A., Ohno,K., Yamaguchi,M. and Cotterill,S. (2001) Nearest neighbour analysis of MCM protein complexes in Drosophila melanogaster. Nucleic Acids Res 29, 4834-4842.

46. Shin,J.H., Heo,G.Y. and Kelman,Z. (2009) The Methanothermobacter thermautotrophicus MCM helicase is active as a hexameric ring. J Biol Chem 284, 540-546.

47. 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.

48. 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.

49. Tanaka,S. and Diffley,J.F. (2002) Interdependent nuclear accumulation of budding yeast Cdt1 and Mcm2-7 during G1 phase. Nat Cell Biol 4, 198-207.

50. Jang,S.W., Elsasser,S., Campbell,J.L. and Kim,J. (2001) Identification of Cdc6 protein domains involved in interaction with Mcm2 protein and Cdc4 protein in budding yeast cells. Biochem J 354, 655-661.

51. 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 Biol8, 358-366.

52. Wysocka,M., Rytka,J. and Kurlandzka,A. (2004) Saccharomyces cerevisiae CSM1 gene encoding a protein influencing chromosome segregation in meiosis I interacts with elements of the DNA replication complex. Exp Cell Res 294, 592-602.

53. Nedelcheva,M.N., Roguev,A., Dolapchiev,L.B., Shevchenko,A., Taskov,H.B., Shevchenko,A., Stewart,A.F. and Stoynov,S.S. (2005) Uncoupling of unwinding from DNA synthesis implies regulation of MCM helicase by Tof1/Mrc1/Csm3 checkpoint complex. J Mol Biol 347, 509-521.

54. Burke,T.W., Cook,J.G., Asano,M. and Nevins,J.R. (2001) Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. J Biol Chem 276, 15397-15408.

55. 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.

56. 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.

57. Yamada,Y., Nakagawa,T. and Masukata,H. (2004) A novel intermediate in initiation complex assembly for fission yeast DNA replication. Mol Biol Cell 15, 3740-3750.

58. Bailis,J.M., Luche,D.D., Hunter,T. and Forsburg,S.L. (2008) Minichromosome maintenance proteins interact with checkpoint and recombination proteins to promote s-phase genome stability. Mol Cell Biol 28, 1724-1738.

59. Ferenbach,A., Li,A., Brito-Martins,M. and Blow,J.J. (2005) Functional domains of the Xenopus replication licensing factor Cdt1. Nucleic Acids Res 33, 316-324.

60. Yankulov,K., Todorov,I., Romanowski,P., Licatalosi,D., Cilli,K., McCracken,S., Laskey,R. and Bentley,D.L. (1999) MCM proteins are associated with RNA polymerase II holoenzyme. Mol Cell Biol 19, 6154-6163.

61. Pacek,M. and Walter,J.C. (2004) A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J 23, 3667-3676.

62. Masuda,T., Mimura,S. and Takisawa,H. (2003) CDK- and Cdc45-dependent priming of the MCM complex on chromatin during S-phase in Xenopus egg extracts: possible activation of MCM helicase by association with Cdc45. Genes Cells 8, 145-161.

63. Gillespie,P.J., Khoudoli,G.A., Stewart,G., Swedlow,J.R. and Blow,J.J. (2007) ELYS/MEL-28 chromatin association coordinates nuclear pore complex assembly and replication licensing. Curr Biol 17, 1657-1662.

64. Cook,J.G., Chasse,D.A. and Nevins,J.R. (2004) The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. J Biol Chem 279, 9625-9633.

65. Yanagi,K., Mizuno,T., You,Z. and Hanaoka,F. (2002) Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity. J Biol Chem 277, 40871-40880.

66. You,Z. and Masai,H. (2008) Cdt1 forms a complex with the minichromosome maintenance protein (MCM) and activates its helicase activity. J Biol Chem 283, 24469-24477.

67. Gauthier,L., Dziak,R., Kramer,D.J., Leishman,D., Song,X., Ho,J., Radovic,M., Bentley,D. and Yankulov,K. (2002) The role of the carboxyterminal domain of RNA polymerase II in regulating origins of DNA replication in Saccharomyces cerevisiae. Genetics 162, 1117-1129.

68. Holland,L., Gauthier,L., Bell-Rogers,P. and Yankulov,K. (2002) Distinct parts of minichromosome maintenance protein 2 associate with histone H3/H4 and RNA polymerase II holoenzyme. Eur J Biochem 269, 5192-5202.

69. Tsvetkov,L. and Stern,D.F. (2005) Interaction of chromatin-associated Plk1 and Mcm7. J Biol Chem 280, 11943-11947.

70. Trenz,K., Errico,A. and Costanzo,V. (2008) Plx1 is required for chromosomal DNA replication under stressful conditions. EMBO J 27, 876-885.

71. Ishimi,Y., Ichinose,S., Omori,A., Sato,K. and Kimura,H. (1996) Binding of human minichromosome maintenance proteins with histone H3. J Biol Chem 271, 24115-24122.

72. Pereverzeva,I., Whitmire,E., Khan,B. and Coue,M. (2000) Distinct phosphoisoforms of the Xenopus Mcm4 protein regulate the function of the Mcm complex. Mol Cell Biol 20, 3667-3676.

73. Ryu,M.J., Kim,B.J., Lee,J.W., Lee,M.W., Choi,H.K. and Kim,S.T. (2006) Direct interaction between cohesin complex and DNA replication machinery. Biochem Biophys Res Commun 341, 770-775.

74. Tan,B.C., Chien,C.T., Hirose,S. and Lee,S.C. (2006) Functional cooperation between FACT and MCM helicase facilitates initiation of chromatin DNA replication. EMBO J25, 3975-3985.

75. Shukla,A., Navadgi,V.M., Mallikarjuna,K. and Rao,B.J. (2005) Interaction of hRad51 and hRad52 with MCM complex: a cross-talk between recombination and replication proteins. Biochem Biophys Res Commun 329, 1240-1245.

76. Eide,T., Tasken,K.A., Carlson,C., Williams,G., Jahnsen,T., Tasken,K. and Collas,P. (2003) Protein kinase A-anchoring protein AKAP95 interacts with MCM2, a regulator of DNA replication. J Biol Chem 278, 26750-26756.

77. Nallamshetty,S., Crook,M., Boehm,M., Yoshimoto,T., Olive,M. and Nabel,E.G. (2005) The cell cycle regulator p27Kip1 interacts with MCM7, a DNA replication licensing factor, to inhibit initiation of DNA replication. FEBS Lett 579, 6529-6536.

78. Sakwe,A.M., Nguyen,T., Athanasopoulos,V., Shire,K. and Frappier,L. (2007) Identification and characterization of a novel component of the human minichromosome maintenance complex. Mol Cell Biol 27, 3044-3055.

79. Buchsbaum,S., Morris,C., Bochard,V. and Jalinot,P. (2007) Human INT6 interacts with MCM7 and regulates its stability during S phase of the cell cycle. Oncogene26, 5132-5144.

80. Kim,B.J. and Lee,H. (2008) Caspase-mediated cleavage of importin-alpha increases its affinity for MCM and downregulates DNA synthesis by interrupting the binding of MCM to chromatin. Biochim Biophys Acta 1783, 2287-2293.

81. Takahashi,N., Lammens,T., Boudolf,V., Maes,S., Yoshizumi,T., De Jaeger,G., Witters,E., Inze,D. and De Veylder,L. (2008) The DNA replication checkpoint aids survival of plants deficient in the novel replisome factor ETG1. EMBO J 27, 1840-1851.

82. Marinsek,N., Barry,E.R., Makarova,K.S., Dionne,I., Koonin,E.V. and Bell,S.D. (2006) GINS, a central nexus in the archaeal DNA replication fork. EMBO Rep 7, 539-545.

83. Kawaguchi,A. and Nagata,K. (2007) De novo replication of the influenza virus RNA genome is regulated by DNA replicative helicase, MCM. EMBO J 26, 4566-4575.

84. Braun,K.A. and Breeden,L.L. (2007) Nascent transcription of MCM2-7 is important for nuclear localization of the minichromosome maintenance complex in G1. Mol Biol Cell 18, 1447-1456.

85. Charych,D.H., Coyne,M., Yabannavar,A., Narberes,J., Chow,S., Wallroth,M., Shafer,C. and Walter,A.O. (2008) Inhibition of Cdc7/Dbf4 kinase activity affects specific phosphorylation sites on MCM2 in cancer cells. J Cell Biochem 104, 1075-1086.

86. Kelman,Z. and Hurwitz,J. (2003) Structural lessons in DNA replication from the third domain of life. Nat Struct Biol 10, 148-150.

87. Liu,W., Pucci,B., Rossi,M., Pisani,F.M. and Ladenstein,R. (2008) Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain. Nucleic Acids Res 36, 3235-3243.

88. Costa,A., van Duinen,G., Medagli,B., Chong,J., Sakakibara,N., Kelman,Z., Nair,S.K., Patwardhan,A. and Onesti,S. (2008) Cryo-electron microscopy reveals a novel DNA-binding site on the MCM helicase. EMBO J 27, 2250-2258.

89. Leon,R.P., Tecklenburg,M. and Sclafani,R.A. (2008) Functional conservation of beta-hairpin DNA binding domains in the Mcm protein of Methanobacterium thermoautotrophicum and the Mcm5 protein of Saccharomyces cerevisiae. Genetics179, 1757-1768.

90. Brewster,A.S., Wang,G., Yu,X., Greenleaf,W.B., Carazo,J.M., Tjajadia,M., Klein,M.G. and Chen,X.S. (2008) Crystal structure of a near-full-length archaeal MCM: functional insights for an AAA+ hexameric helicase. Proc Natl Acad Sci U S A 105, 20191-20196.

91. Labib,K., Diffley,J.F. and Kearsey,S.E. (1999) G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nat Cell Biol 1, 415-422.

92. Nguyen,V.Q., Co,C., Irie,K. and Li,J.J. (2000) Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins Mcm2-7. Curr Biol 10, 195-205.

93. Maiorano,D., Van Assendelft,G.B. and Kearsey,S.E. (1996) Fission yeast cdc21, a member of the MCM protein family, is required for onset of S phase and is located in the nucleus throughout the cell cycle. EMBO J 15, 861-872.

94. Namdar,M. and Kearsey,S.E. (2006) Analysis of Mcm2-7 chromatin binding during anaphase and in the transition to quiescence in fission yeast. Exp Cell Res 312, 3360-3369.

95. Pasion,S.G. and Forsburg,S.L. (1999) Nuclear localization of Schizosaccharomyces pombe Mcm2/Cdc19p requires MCM complex assembly. Mol Biol Cell 10, 4043-4057.

96. Crevel,G., Hashimoto,R., Vass,S., Sherkow,J., Yamaguchi,M., Heck,M.M. and Cotterill,S. (2007) Differential requirements for MCM proteins in DNA replication in Drosophila S2 cells. PLoS ONE 2, e833.

97. Maiorano,D., Lemaitre,J.M. and Mechali,M. (2000) Stepwise regulated chromatin assembly of MCM2-7 proteins. J Biol Chem 275, 8426-8431.

98. Ekholm-Reed,S., Mendez,J., Tedesco,D., Zetterberg,A., Stillman,B. and Reed,S.I. (2004) Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J Cell Biol 165, 789-800.

99. Noguchi,K., Vassilev,A., Ghosh,S., Yates,J.L. and DePamphilis,M.L. (2006) The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J 25, 5372-5382.

100. Perkins,G. and Diffley,J.F. (1998) Nucleotide-dependent prereplicative complex assembly by Cdc6p, a homolog of eukaryotic and prokaryotic clamp-loaders. Mol Cell 2, 23-32.

101. Mahbubani,H.M., Chong,J.P., Chevalier,S., Thommes,P. and Blow,J.J. (1997) Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor. J Cell Biol 136, 125-135.

102. Oehlmann,M., Score,A.J. and Blow,J.J. (2004) The role of Cdc6 in ensuring complete genome licensing and S phase checkpoint activation. J Cell Biol 165, 181-190.

103. Woodward,A.M., Gohler,T., Luciani,M.G., Oehlmann,M., Ge,X., Gartner,A., Jackson,D.A. and Blow,J.J. (2006) Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol 173, 673-683.

104. Ge,X.Q., Jackson,D.A. and Blow,J.J. (2007) Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev 21, 3331-3341.

105. Laskey,R.A. and Madine,M.A. (2003) A rotary pumping model for helicase function of MCM proteins at a distance from replication forks. EMBO Rep 4, 26-30.

106. Kaplan,D.L., Davey,M.J. and O'Donnell,M. (2003) Mcm4,6,7 uses a "pump in ring" mechanism to unwind DNA by steric exclusion and actively translocate along a duplex. J Biol Chem 278, 49171-49182.

107. Takahashi,T.S., Wigley,D.B. and Walter,J.C. (2005) Pumps, paradoxes and ploughshares: mechanism of the MCM2-7 DNA helicase. Trends Biochem Sci 30, 437-444.

108. Fitch,M.J., Donato,J.J. and Tye,B.K. (2003) Mcm7, a subunit of the presumptive MCM helicase, modulates its own expression in conjunction with Mcm1. J Biol Chem 278, 25408-25416.

109. Dziak,R., Leishman,D., Radovic,M., Tye,B.K. and Yankulov,K. (2003) Evidence for a role of MCM (mini-chromosome maintenance)5 in transcriptional repression of sub-telomeric and Ty-proximal genes in Saccharomyces cerevisiae. J Biol Chem 278, 27372-27381.

110. Ishimi,Y., Okayasu,I., Kato,C., Kwon,H.J., Kimura,H., Yamada,K. and Song,S.Y. (2003) Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Eur J Biochem 270, 1089-1101.

111. Nitani,N., Nakamura,K., Nakagawa,C., Masukata,H. and Nakagawa,T. (2006) Regulation of DNA replication machinery by Mrc1 in fission yeast. Genetics 174, 155-165.

112. Ibarra,A., Schwob,E. and Mendez,J. (2008) Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc Natl Acad Sci U S A 105, 8956-8961.

113. McGeoch,A.T., Trakselis,M.A., Laskey,R.A. and Bell,S.D. (2005) Organization of the archaeal MCM complex on DNA and implications for the helicase mechanism. Nat Struct Mol Biol 12, 756-762.

114. Matsunaga,F., Glatigny,A., Mucchielli-Giorgi,M.H., Agier,N., Delacroix,H., Marisa,L., Durosay,P., Ishino,Y., Aggerbeck,L. and Forterre,P. (2007) Genomewide and biochemical analyses of DNA-binding activity of Cdc6/Orc1 and Mcm proteins in Pyrococcus sp. Nucleic Acids Res35, 3214-3222.

115. Sakakibara,N., Kasiviswanathan,R., Melamud,E., Han,M., Schwarz,F.P. and Kelman,Z. (2008) Coupling of DNA binding and helicase activity is mediated by a conserved loop in the MCM protein. Nucleic Acids Res 36, 1309-1320.

116. Haugland,G.T., Sakakibara,N., Pey,A.L., Rollor,C.R., Birkeland,N.K. and Kelman,Z. (2008) Thermoplasma acidophilum Cdc6 protein stimulates MCM helicase activity by regulating its ATPase activity. Nucleic Acids Res 36, 5602-5609.

117. Komamura-Kohno,Y., Tanaka,R., Omori,A., Kohno,T. and Ishimi,Y. (2008) Biochemical characterization of fragmented human MCM2. FEBS J 275, 727-738.

118. Liku,M.E., Nguyen,V.Q., Rosales,A.W., Irie,K. and Li,J.J. (2005) CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2-7 complex prevents chromosomal rereplication. Mol Biol Cell 16, 5026-5039.

119. Gavin,A.C., Bosche,M., Krause,R., Grandi,P., Marzioch,M., Bauer,A., Schultz,J., Rick,J.M., Michon,A.M., Cruciat,C.M., Remor,M., Hofert,C., Schelder,M., Brajenovic,M., Ruffner,H., Merino,A., Klein,K., Hudak,M., Dickson,D., Rudi,T., Gnau,V., Bauch,A., Bastuck,S., Huhse,B., Leutwein,C., Heurtier,M.A., Copley,R.R., Edelmann,A., Querfurth,E., Rybin,V., Drewes,G., Raida,M., Bouwmeester,T., Bork,P., Seraphin,B., Kuster,B., Neubauer,G. and Superti-Furga,G. (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141-147.

120. 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.

121. Montagnoli,A., Valsasina,B., Brotherton,D., Troiani,S., Rainoldi,S., Tenca,P., Molinari,A. and Santocanale,C. (2006) Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases. J Biol Chem 281, 10281-10290.

122. Cortez,D., Glick,G. and Elledge,S.J. (2004) Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci U S A 101, 10078-10083.

123. Young,M.R. and Tye,B.K. (1997) Mcm2 and Mcm3 are constitutive nuclear proteins that exhibit distinct isoforms and bind chromatin during specific cell cycle stages of Saccharomyces cerevisiae. Mol Biol Cell 8, 1587-1601.

124. Yoo,H.Y., Shevchenko,A., Shevchenko,A. and Dunphy,W.G. (2004) Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J Biol Chem 279, 53353-53364.

125. Fujita,M., Yamada,C., Tsurumi,T., Hanaoka,F., Matsuzawa,K. and Inagaki,M. (1998) Cell cycle- and chromatin binding state-dependent phosphorylation of human MCM heterohexameric complexes. A role for cdc2 kinase. J Biol Chem 273, 17095-17101.

126. 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.

127. Harada,H., Nakagawa,H., Takaoka,M., Lee,J., Herlyn,M., Diehl,J.A. and Rustgi,A.K. (2008) Cleavage of MCM2 licensing protein fosters senescence in human keratinocytes. Cell Cycle 7, 3534-3538.

128. Tye,B.K. (1994) The MCM2-3-5 proteins: are they replication licensing factors? Trends Cell Biol 4, 160-166.

129. Lin,D.I., Aggarwal,P. and Diehl,J.A. (2008) Phosphorylation of MCM3 on Ser-112 regulates its incorporation into the MCM2-7 complex. Proc Natl Acad Sci U S A 105, 8079-8084.

130. Takei,Y. and Tsujimoto,G. (1998) Identification of a novel MCM3-associated protein that facilitates MCM3 nuclear localization. J Biol Chem 273, 22177-22180.

131. Kono,Y., Maeda,K., Kuwahara,K., Yamamoto,H., Miyamoto,E., Yonezawa,K., Takagi,K. and Sakaguchi,N. (2002) MCM3-binding GANP DNA-primase is associated with a novel phosphatase component G5PR. Genes Cells 7, 821-834.

132. Ishimi,Y., Komamura-Kohno,Y., Arai,K. and Masai,H. (2001) Biochemical activities associated with mouse Mcm2 protein. J Biol Chem 276, 42744-42752.

133. Takei,Y., Assenberg,M., Tsujimoto,G. and Laskey,R. (2002) The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with MCM3. J Biol Chem 277, 43121-43125.

134. Cheng,I.H., Roberts,L.A. and Tye,B.K. (2002) Mcm3 is polyubiquitinated during mitosis before establishment of the pre-replication complex. J Biol Chem 277, 41706-41714.

135. Madine,M.A., Khoo,C.Y., Mills,A.D., Musahl,C. and Laskey,R.A. (1995) The nuclear envelope prevents reinitiation of replication by regulating the binding of MCM3 to chromatin in Xenopus egg extracts. Curr Biol 5, 1270-1279.

136. Shi,Y., Dodson,G.E., Mukhopadhyay,P.S., Shanware,N.P., Trinh,A.T. and Tibbetts,R.S. (2007) Identification of carboxyl-terminal MCM3 phosphorylation sites using polyreactive phosphospecific antibodies. J Biol Chem 282, 9236-9243.

137. Musahl,C., Holthoff,H.P., Lesch,R. and Knippers,R. (1998) Stability of the replicative Mcm3 protein in proliferating and differentiating human cells. Exp Cell Res 241, 260-264.

138. Yim,H., Hwang,I.S., Choi,J.S., Chun,K.H., Jin,Y.H., Ham,Y.M., Lee,K.Y. and Lee,S.K. (2006) Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. J Cell Biol 174, 77-88.

139. Nitani,N., Yadani,C., Yabuuchi,H., Masukata,H. and Nakagawa,T. (2008) Mcm4 C-terminal domain of MCM helicase prevents excessive formation of single-stranded DNA at stalled replication forks. Proc Natl Acad Sci U S A 105, 12973-12978.

140. 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 Dev14, 913-926.

141. 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.

142. Schmitz,N.M., Leibundgut,K. and Hirt,A. (2004) MCM4 shares homology to a replication/DNA-binding domain in CTF and is contacted by pRb. Biochem Biophys Res Commun 317, 779-786.

143. Ishimi,Y., Komamura-Kohno,Y., Kwon,H.J., Yamada,K. and Nakanishi,M. (2003) Identification of MCM4 as a target of the DNA replication block checkpoint system. J Biol Chem 278, 24644-24650.

144. Devault,A., Gueydon,E. and Schwob,E. (2008) Interplay between S-cyclin-dependent kinase and Dbf4-dependent kinase in controlling DNA replication through phosphorylation of yeast Mcm4 N-terminal domain. Mol Biol Cell 19, 2267-2277.

145. Coue,M., Kearsey,S.E. and Mechali,M. (1996) Chromotin binding, nuclear localization and phosphorylation of Xenopus cdc21 are cell-cycle dependent and associated with the control of initiation of DNA replication. EMBO J 15, 1085-1097.

146. Hendrickson,M., Madine,M., Dalton,S. and Gautier,J. (1996) Phosphorylation of MCM4 by cdc2 protein kinase inhibits the activity of the minichromosome maintenance complex. Proc Natl Acad Sci U S A93, 12223-12228.

147. Komamura-Kohno,Y., Karasawa-Shimizu,K., Saitoh,T., Sato,M., Hanaoka,F., Tanaka,S. and Ishimi,Y. (2006) Site-specific phosphorylation of MCM4 during the cell cycle in mammalian cells. FEBS J 273, 1224-1239.

148. Ishimi,Y., Komamura-Kohno,Y., Karasawa-Shimizu,K. and Yamada,K. (2004) Levels of MCM4 phosphorylation and DNA synthesis in DNA replication block checkpoint control. J Struct Biol 146, 234-241.

149. Kudoh,A., Daikoku,T., Ishimi,Y., Kawaguchi,Y., Shirata,N., Iwahori,S., Isomura,H. and Tsurumi,T. (2006) Phosphorylation of MCM4 at sites inactivating DNA helicase activity of the MCM4-MCM6-MCM7 complex during Epstein-Barr virus productive replication. J Virol 80, 10064-10072.

150. Shima,N., Alcaraz,A., Liachko,I., Buske,T.R., Andrews,C.A., Munroe,R.J., Hartford,S.A., Tye,B.K. and Schimenti,J.C. (2007) A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet 39, 93-98.

151. Hoang,M.L., Leon,R.P., Pessoa-Brandao,L., Hunt,S., Raghuraman,M.K., Fangman,W.L., Brewer,B.J. and Sclafani,R.A. (2007) Structural changes in Mcm5 protein bypass Cdc7-Dbf4 function and reduce replication origin efficiency in Saccharomyces cerevisiae. Mol Cell Biol 27, 7594-7602.

152. Zhang,J.J., Zhao,Y., Chait,B.T., Lathem,W.W., Ritzi,M., Knippers,R. and Darnell,J.E.J. (1998) Ser727-dependent recruitment of MCM5 by Stat1alpha in IFN-gamma-induced transcriptional activation. EMBO J 17, 6963-6971.

153. Snyder,M., He,W. and Zhang,J.J. (2005) The DNA replication factor MCM5 is essential for Stat1-mediated transcriptional activation. Proc Natl Acad Sci U S A 102, 14539-14544.

154. DaFonseca,C.J., Shu,F. and Zhang,J.J. (2001) Identification of two residues in MCM5 critical for the assembly of MCM complexes and Stat1-mediated transcription activation in response to IFN-gamma. Proc Natl Acad Sci U S A 98, 3034-3039.

155. Ferguson,R.L. and Maller,J.L. (2008) Cyclin E-dependent localization of MCM5 regulates centrosome duplication. J Cell Sci121, 3224-3232.

156. Lake,C.M., Teeter,K., Page,S.L., Nielsen,R. and Hawley,R.S. (2007) A genetic analysis of the Drosophila mcm5 gene defines a domain specifically required for meiotic recombination. Genetics176, 2151-2163.

157. Wang,X., Suh,C., Zhu,Z. and Fan,Q. (2007) Minichromosome maintenance protein 5 homologue in Caenorhabditis elegans plays essential role for postembryonic development. Biochem Biophys Res Commun 359, 965-971.

158. Hayashi,M., Katou,Y., Itoh,T., Tazumi,A., Yamada,Y., Takahashi,T., Nakagawa,T., Shirahige,K. and Masukata,H. (2007) Genome-wide localization of pre-RC sites and identification of replication origins in fission yeast. EMBO J 26, 1327-1339.

159. Liang,D.T., Hodson,J.A. and Forsburg,S.L. (1999) Reduced dosage of a single fission yeast MCM protein causes genetic instability and S phase delay. J Cell Sci 112, 559-567.

160. Sterner,J.M., Dew-Knight,S., Musahl,C., Kornbluth,S. and Horowitz,J.M. (1998) Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7. Mol Cell Biol 18, 2748-2757.

161. Wang,Y., Xu,F. and Hall,F.L. (2000) The MAT1 cyclin-dependent kinase-activating kinase (CAK) assembly/targeting factor interacts physically with the MCM7 DNA licensing factor. FEBS Lett 484, 17-21.

162. Tsao,C.C., Geisen,C. and Abraham,R.T. (2004) Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling. EMBO J 23, 4660-4669.

163. Fujita,M., Kiyono,T., Hayashi,Y. and Ishibashi,M. (1996) hCDC47, a human member of the MCM family. Dissociation of the nucleus-bound form during S phase. J Biol Chem 271, 4349-4354.

164. Parlanti,E., Locatelli,G., Maga,G. and Dogliotti,E. (2007) Human base excision repair complex is physically associated to DNA replication and cell cycle regulatory proteins. Nucleic Acids Res 35, 1569-1577.

165. Kuhne,C. and Banks,L. (1998) E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box. J Biol Chem 273, 34302-34309.

166. Honeycutt,K.A., Chen,Z., Koster,M.I., Miers,M., Nuchtern,J., Hicks,J., Roop,D.R. and Shohet,J.M. (2006) Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis. Oncogene 25, 4027-4032.

167. Yoshida,K. and Inoue,I. (2003) Conditional expression of MCM7 increases tumor growth without altering DNA replication activity. FEBS Lett 553, 213-217.

168. Padmanabhan,V., Callas,P., Philips,G., Trainer,T.D. and Beatty,B.G. (2004) DNA replication regulation protein Mcm7 as a marker of proliferation in prostate cancer. J Clin Pathol 57, 1057-1062.

169. Brake,T., Connor,J.P., Petereit,D.G. and Lambert,P.F. (2003) Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer. Cancer Res 63, 8173-8180.

170. Cromer,A., Carles,A., Millon,R., Ganguli,G., Chalmel,F., Lemaire,F., Young,J., Dembele,D., Thibault,C., Muller,D., Poch,O., Abecassis,J. and Wasylyk,B. (2004) Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene 23, 2484-2498.

171. Grutzmann,R., Pilarsky,C., Ammerpohl,O., Luttges,J., Bohme,A., Sipos,B., Foerder,M., Alldinger,I., Jahnke,B., Schackert,H.K., Kalthoff,H., Kremer,B., Kloppel,G. and Saeger,H.D. (2004) Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia 6, 611-622.

172. Shohet,J.M., Hicks,M.J., Plon,S.E., Burlingame,S.M., Stuart,S., Chen,S.Y., Brenner,M.K. and Nuchtern,J.G. (2002) Minichromosome maintenance protein MCM7 is a direct target of the MYCN transcription factor in neuroblastoma. Cancer Res 62, 1123-1128.

173. Ren,B., Yu,G., Tseng,G.C., Cieply,K., Gavel,T., Nelson,J., Michalopoulos,G., Yu,Y.P. and Luo,J.H. (2006) MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene 25, 1090-1098.

174. Yoshida,K. and Inoue,I. (2004) Regulation of Geminin and Cdt1 expression by E2F transcription factors. Oncogene 23, 3802-3812.

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