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Chromosoma

, Volume 122, Issue 1–2, pp 47–53 | Cite as

Structure and evolutionary origins of the CMG complex

  • Silvia Onesti
  • Stuart A. MacNeillEmail author
Mini-Review

Abstract

The CMG (Cdc45–MCM–GINS) complex is the eukaryotic replicative helicase, the enzyme that unwinds double-stranded DNA at replication forks. All three components of the CMG complex are essential for its function, but only in the case of MCM, the molecular motor that harnesses the energy of ATP hydrolysis to catalyse strand separation, is that function clear. Here, we review current knowledge of the three-dimensional structure of the CMG complex and its components and highlight recent advances in our understanding of its evolutionary origins.

Keywords

DNA replication DNA helicase CMG MCM GINS Cdc45 

Notes

Acknowledgments

We thank our colleagues in St Andrews, Trieste and elsewhere for their help in the preparation of this review. Work in our laboratories is funded by the Scottish Universities Life Sciences Alliance (SULSA) and by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG10646).

References

  1. Aravind L, Koonin EV (1998) A novel family of predicted phosphoesterases includes Drosophila prune protein and bacterial RecJ exonuclease. Trends Biochem Sci 23:17–19PubMedCrossRefGoogle Scholar
  2. Aves SJ, Liu Y, Richards TA (2012) Evolutionary diversification of eukaryotic DNA replication machinery. Subcell Biochem 62:19–35PubMedCrossRefGoogle Scholar
  3. Bae B, Chen Y-H, Costa A et al (2009) Insights into the architecture of the replicative helicase from the structure of an archaeal MCM homolog. Structure 17:211–222PubMedCrossRefGoogle Scholar
  4. Bochman ML, Schwacha A (2008) The Mcm2-7 complex has in vitro helicase activity. Mol Cell 31:287–293PubMedCrossRefGoogle Scholar
  5. Boos D, Frigola J, Diffley JF (2012) Activation of the replicative DNA helicase: breaking up is hard to do. Curr Opin Cell Biol 24:324–430CrossRefGoogle Scholar
  6. Boskovic J, Coloma J, Aparicio T et al (2007) Molecular architecture of the human GINS complex. EMBO Rep 8:678–684PubMedCrossRefGoogle Scholar
  7. Bowers JL, Randell JCW, Chen S et al (2004) ATP hydrolysis by ORC catalyzes reiterative Mcm2-7 assembly at a defined origin of replication. Mol Cell 16:967–978PubMedCrossRefGoogle Scholar
  8. Brewster AS, Wang G, Yu X et al (2008) Crystal structure of a near-full-length archaeal MCM: functional insights for an AAA+ hexameric helicase. Proc Natl Acad Sci U S A 105:20191–20196PubMedCrossRefGoogle Scholar
  9. Chang YP, Wang G, Bermudez V et al (2007) Crystal structure of the GINS complex and functional insights into its role in DNA replication. Proc Natl Acad Sci U S A 104:12685–12690PubMedCrossRefGoogle Scholar
  10. Chen YJ, Yu X, Kasiviswanathan R et al (2005) Structural polymorphism of Methanothermobacter thermautotrophicus MCM. J Mol Biol 346:389–394PubMedCrossRefGoogle Scholar
  11. Choi JM, Lim HS, Kim JJ et al (2007) Crystal structure of the human GINS complex. Genes Dev 21:1316–1321PubMedCrossRefGoogle Scholar
  12. Costa A, Onesti S (2008) The MCM complex: (just) a replicative helicase? Biochem Soc Trans 36:136–140PubMedCrossRefGoogle Scholar
  13. Costa A, Onesti S (2009) Structural biology of MCM helicases. Crit Rev Biochem Mol Biol 44:326–342PubMedCrossRefGoogle Scholar
  14. Costa A, Pape T, van Heel M et al (2006) Structural basis of the Methanothermobacter thermautotrophicus MCM helicase activity. Nucleic Acids Res 34:5829–5838PubMedCrossRefGoogle Scholar
  15. Costa A, van Duinen G, Medagli B et al (2008) Cryo-electron microscopy reveals a novel DNA-binding site on the MCM helicase. EMBO J 27:2250–2258PubMedCrossRefGoogle Scholar
  16. Costa A, Ilves I, Tamberg N et al (2011) The structural basis for MCM2–7 helicase activation by GINS and Cdc45. Nat Struct Mol Biol 18:471–477PubMedCrossRefGoogle Scholar
  17. Duderstadt K, Berger J (2008) AAA+ ATPases in the Initiation of DNA Replication. Crit Rev Biochem Mol Biol 43:163–187PubMedCrossRefGoogle Scholar
  18. Evrin C, Clarke P, Zech J et al (2009) A double-hexameric MCM2–7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. Proc Natl Acad Sci U S A 106:20240–20245PubMedCrossRefGoogle Scholar
  19. Fletcher RJ, Bishop BE, Leon RP et al (2003) The structure and function of MCM from archaeal M. thermoautotrophicum. Nat Struct Biol 10:160–167PubMedCrossRefGoogle Scholar
  20. Fu YV, Yardimci H, Long DT et al (2011) Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146:931–941PubMedCrossRefGoogle Scholar
  21. Gambus A, Jones RC, Sanchez-Diaz A et al (2006) GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol 8:358–366PubMedCrossRefGoogle Scholar
  22. Gómez-Llorente Y, Fletcher RJ, Chen XS et al (2005) Polymorphism and double hexamer structure in the archaeal minichromosome maintenance (MCM) helicase from Methanobacterium thermoautotrophicum. J Biol Chem 280:40909–40915PubMedCrossRefGoogle Scholar
  23. Han ES, Cooper DL, Persky NS et al (2006) RecJ exonuclease: substrates, products and interaction with SSB. Nucleic Acids Res 34:1084–1091PubMedCrossRefGoogle Scholar
  24. Hashimoto Y, Puddu F, Costanzo V (2011) RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat Struct Mol Biol 19:17–24PubMedCrossRefGoogle Scholar
  25. Ilves I, Petojevic T, Pesavento JJ, Botchan MR (2010) Activation of the MCM2–7 helicase by association with Cdc45 and GINS proteins. Mol Cell 37:247–258PubMedCrossRefGoogle Scholar
  26. Ishimi Y (1997) A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem 272:24508–24513PubMedCrossRefGoogle Scholar
  27. Jenkinson ER, Costa A, Leech AP et al (2009) Mutations in subdomain B of the minichromosome maintenance (MCM) helicase affect DNA binding and modulate conformational transitions. J Biol Chem 284:5654–5661PubMedCrossRefGoogle Scholar
  28. Kamada K (2012) The GINS complex: structure and function. Subcell Biochem 62:135–156PubMedCrossRefGoogle Scholar
  29. Kamada K, Kubota Y, Arata T et al (2007) Structure of the human GINS complex and its assembly and functional interface in replication initiation. Nat Struct Mol Biol 14:388–396PubMedCrossRefGoogle Scholar
  30. Kamimura Y, Tak YS, Sugino A, Araki H (2001) Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae. EMBO J 20:2097–2107PubMedCrossRefGoogle Scholar
  31. Kanemaki M, Labib K (2006) Distinct roles for Sld3 and GINS during establishment and progression of eukaryotic DNA replication forks. EMBO J 25:1753–1763PubMedCrossRefGoogle Scholar
  32. Krastanova I, Sannino V, Amenitsch H et al (2012) Structural and functional insights into the DNA replication factor Cdc45 reveal an evolutionary relationship to the DHH family of phosphoesterases. J Biol Chem 287:4121–4128PubMedCrossRefGoogle Scholar
  33. Lee JK, Hurwitz J (2000) Isolation and characterization of various complexes of the minichromosome maintenance proteins of Schizosaccharomyces pombe. J Biol Chem 275:18871–18878PubMedCrossRefGoogle Scholar
  34. Leigh JA, Albers S-V, Atomi H, Allers T (2011) Model organisms for genetics in the domain Archaea: methanogens, halophiles, Thermococcales and Sulfolobales. FEMS Microbiol Rev 35:577–608PubMedCrossRefGoogle Scholar
  35. Li H, Stillman B (2012) The origin recognition complex: a biochemical and structural view. Subcell Biochem 62:37–58PubMedCrossRefGoogle Scholar
  36. Li Z, Santangelo TJ, Cuboňová L et al (2010) Affinity purification of an archaeal DNA replication protein network. MBio 1:5CrossRefGoogle Scholar
  37. Li Z, Pan M, Santangelo TJ et al (2011) A novel DNA nuclease is stimulated by association with the GINS complex. Nucleic Acids Res 39:6114–6123PubMedCrossRefGoogle Scholar
  38. Liu W, Pucci B, Rossi M et al (2008) Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain. Nucleic Acids Res 36:3235–3243PubMedCrossRefGoogle Scholar
  39. Liu Y, Richards TA, Aves SJ (2009) Ancient diversification of eukaryotic MCM DNA replication proteins. BMC Evol Biol 9:60PubMedCrossRefGoogle Scholar
  40. Lovett ST, Kolodner RD (1989) Identification and purification of a single-stranded-DNA-specific exonuclease encoded by the recJ gene of Escherichia coli. Proc Natl Acad Sci U S A 86:2627–2631PubMedCrossRefGoogle Scholar
  41. MacNeill SA (2010) Structure and function of the GINS complex, a key component of the eukaryotic replisome. Biochem J 425:489–500PubMedCrossRefGoogle Scholar
  42. Makarova KS, Koonin EV, Kelman Z (2012) The CMG (CDC45/RecJ, MCM, GINS) complex is a conserved component of the DNA replication system in all archaea and eukaryotes. Biol Direct 7:7PubMedCrossRefGoogle Scholar
  43. Marinsek N, Barry ER, Makarova KS et al (2006) GINS, a central nexus in the archaeal DNA replication fork. EMBO Rep 7:539–545PubMedGoogle Scholar
  44. Moyer SE, Lewis PW, Botchan MR (2006) Isolation of the Cdc45/Mcm2–7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase. 103:10236–10241Google Scholar
  45. Muramatsu S, Hirai K, Tak Y-S et al (2010) CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol ε, and GINS in budding yeast. Genes Dev 24:602–612PubMedCrossRefGoogle Scholar
  46. Oyama T, Ishino S, Fujino S et al (2011) Architectures of archaeal GINS complexes, essential DNA replication initiation factors. BMC Biol 9:28PubMedCrossRefGoogle Scholar
  47. Pape T, Meka H, Chen S et al (2003) Hexameric ring structure of the full-length archaeal MCM protein complex. EMBO Rep 4:1079–1083PubMedCrossRefGoogle Scholar
  48. Rajman LA, Lovett ST (2000) A thermostable single-strand DNase from Methanococcus jannaschii related to the RecJ recombination and repair exonuclease from Escherichia coli. J Bacteriol 182:607–612PubMedCrossRefGoogle Scholar
  49. Remus D, Beuron F, Tolun G et al (2010) Concerted loading of Mcm2–7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–730CrossRefGoogle Scholar
  50. Sanchez-Pulido L, Ponting CP (2011) Cdc45: the missing RecJ ortholog in eukaryotes? Bioinformatics 27:1885–1888PubMedCrossRefGoogle Scholar
  51. Slaymaker IM, Chen XS (2012) MCM structure and mechanics: what we have learned from archaeal MCM. Subcell Biochem 62:89–111PubMedCrossRefGoogle Scholar
  52. Snider J, Thibault G, Houry WA (2008) The AAA+ superfamily of functionally diverse proteins. Genome Biol 9:216PubMedCrossRefGoogle Scholar
  53. Sutera VA, Han ES, Rajman LA, Lovett ST (1999) Mutational analysis of the RecJ exonuclease of Escherichia coli: identification of phosphoesterase motifs. J Bacteriol 181:6098–6102PubMedGoogle Scholar
  54. Tanaka S, Umemori T, Hirai K et al (2007) CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature 445:328–332PubMedCrossRefGoogle Scholar
  55. Vijayraghavan S, Schwacha A (2012) The eukaryotic Mcm2–7 replicative helicase. Subcell Biochem 62:113–134PubMedCrossRefGoogle Scholar
  56. Wakamatsu T, Kitamura Y, Kotera Y et al (2010) Structure of RecJ exonuclease defines its specificity for single-stranded DNA. J Biol Chem 285:9762–9769PubMedCrossRefGoogle Scholar
  57. Yamagata A, Kakuta Y, Masui R, Fukuyama K (2002) The crystal structure of exonuclease RecJ bound to Mn2+ ion suggests how its characteristic motifs are involved in exonuclease activity. Proc Natl Acad Sci U S A 99:5908–5912PubMedCrossRefGoogle Scholar
  58. Yu X, VanLoock MS, Poplawski A et al (2002) The Methanobacterium thermoautotrophicum MCM protein can form heptameric rings. EMBO Rep 3:792–797PubMedCrossRefGoogle Scholar
  59. Zegerman P, Diffley JFX (2007) Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature 445:281–285PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Structural Biology LaboratoryElettra-Sincrotrone TriesteTriesteItaly
  2. 2.Biomedical Sciences Research ComplexUniversity of St AndrewsSt AndrewsUK

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