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Annual Review of Biochemistry

Volume 91, 2022

The Initiation of Eukaryotic DNA Replication

Abstract

DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly controlled to ensure the entire genome is precisely duplicated in each cell cycle. This is accomplished through the regulation of the first two steps in replication: loading and activation of the replicative DNA helicase. Here we describe what is known about the mechanism and regulation of these two reactions from a genetic, biochemical, and structural perspective, focusing on recent progress using proteins from budding yeast.

Keyword(s): cell cycle, cryo–electron microscopy, DNA replication
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2022-06-21
2024-04-19
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Literature Cited

  1. 1.
    Mott ML, Berger JM. 2007. DNA replication initiation: mechanisms and regulation in bacteria. Nat. Rev. Microbiol. 5:343–54
     [Google Scholar]
  2. 2.
    Nasir A, Mughal F, Caetano-Anollés G. 2021. The tree of life describes a tripartite cellular world. BioEssays 43:e2000343
     [Google Scholar]
  3. 3.
    Greci MD, Bell SD. 2020. Archaeal DNA replication. Annu. Rev. Microbiol 74:65–80
     [Google Scholar]
  4. 4.
    Singleton MR, Dillingham MS, Wigley DB. 2007. Structure and mechanism of helicases and nucleic acid translocases. Annu. Rev. Biochem. 76:23–50
     [Google Scholar]
  5. 5.
    Kapuy O, He E, López-Avilés S, Uhlmann F, Tyson JJ, Novák B. 2009. System-level feedbacks control cell cycle progression. FEBS Lett 583:3992–98
     [Google Scholar]
  6. 6.
    Vouzas AE, Gilbert DM. 2021. Mammalian DNA replication timing. Cold Spring Harb. Perspect. Biol. In press. https://doi.org/10.1101/cshperspect.a040162
    [Google Scholar]
  7. 7.
    Schmit M, Bielinsky AK. 2021. Congenital diseases of DNA replication: clinical phenotypes and molecular mechanisms. Int. J. Mol. Sci. 22:911
     [Google Scholar]
  8. 8.
    Hills SA, Diffley JFX. 2014. DNA replication and oncogene-induced replicative stress. Curr. Biol. 24:R435–44
     [Google Scholar]
  9. 9.
    Evrin C, Clarke P, Zech J, Lurz R, Sun J et al. 2009. A double-hexameric MCM2–7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. PNAS 106:20240–45
     [Google Scholar]
  10. 10.
    Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JFX. 2009. Concerted loading of Mcm2–7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–30
     [Google Scholar]
  11. 11.
    Yeeles JT, Deegan TD, Janska A, Early A, Diffley JFX. 2015. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 519:431–35
     [Google Scholar]
  12. 12.
    Stinchcomb DT, Struhl K, Davis RW. 1979. Isolation and characterisation of a yeast chromosomal replicator. Nature 282:39–43
     [Google Scholar]
  13. 13.
    Hsiao CL, Carbon J. 1979. High-frequency transformation of yeast by plasmids containing the cloned yeast ARG4 gene. PNAS 76:3829–33
     [Google Scholar]
  14. 14.
    Struhl K, Stinchcomb DT, Scherer S, Davis RW. 1979. High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules. PNAS 76:1035–39
     [Google Scholar]
  15. 15.
    Tschumper G, Carbon J. 1980. Sequence of a yeast DNA fragment containing a chromosomal replicator and the TRP1 gene. Gene 10:157–66
     [Google Scholar]
  16. 16.
    Brewer BJ, Fangman WL. 1987. The localization of replication origins on ARS plasmids in S. cerevisiae. Cell 51:463–71
     [Google Scholar]
  17. 17.
    Huberman JA, Spotila LD, Nawotka KA, El Assouli SM, Davis LR 1987. The in vivo replication origin of the yeast 2 micron plasmid. Cell 51:473–81
     [Google Scholar]
  18. 18.
    Saffer LD, Miller OL Jr. 1986. Electron microscopic study of Saccharomyces cerevisiae rDNA chromatin replication. Mol. Cell. Biol. 6:1148–57
     [Google Scholar]
  19. 19.
    Chang F, Theis JF, Miller J, Nieduszynski CA, Newlon CS, Weinreich M. 2008. Analysis of chromosome III replicators reveals an unusual structure for the ARS318 silencer origin and a conserved WTW sequence within the origin recognition complex binding site. Mol. Cell. Biol. 28:5071–81
     [Google Scholar]
  20. 20.
    Kearsey S. 1984. Structural requirements for the function of a yeast chromosomal replicator. Cell 37:299–307
     [Google Scholar]
  21. 21.
    Srienc F, Bailey JE, Campbell JL. 1985. Effect of ARS1 mutations on chromosome stability in Saccharomyces cerevisiae. Mol. Cell. Biol. 5:1676–84
     [Google Scholar]
  22. 22.
    Coster G, Diffley JFX. 2017. Bidirectional eukaryotic DNA replication is established by quasi-symmetrical helicase loading. Science 357:314–18
     [Google Scholar]
  23. 23.
    Bell SP, Stillman B. 1992. ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature 357:128–34
     [Google Scholar]
  24. 24.
    Diffley JFX, Cocker JH. 1992. Protein-DNA interactions at a yeast replication origin. Nature 357:169–72
     [Google Scholar]
  25. 25.
    Foss M, McNally FJ, Laurenson P, Rine J. 1993. Origin recognition complex (ORC) in transcriptional silencing and DNA replication in S. cerevisiae. Science 262:1838–44
     [Google Scholar]
  26. 26.
    Bell SP, Kobayashi R, Stillman B. 1993. Yeast origin recognition complex functions in transcription silencing and DNA replication. Science 262:1844–49
     [Google Scholar]
  27. 27.
    Bell SP, Mitchell J, Leber J, Kobayashi R, Stillman B. 1995. The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell 83:563–68
     [Google Scholar]
  28. 28.
    Loo S, Fox CA, Rine J, Kobayashi R, Stillman B, Bell S. 1995. The origin recognition complex in silencing, cell-cycle progression, and DNA replication. Mol. Biol. Cell 6:741–56
     [Google Scholar]
  29. 29.
    Micklem G, Rowley A, Harwood J, Nasmyth K, Diffley JFX. 1993. Yeast origin recognition complex is involved in DNA replication and transcriptional silencing. Nature 366:87–89
     [Google Scholar]
  30. 30.
    Li JJ, Herskowitz I. 1993. Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science 262:1870–74
     [Google Scholar]
  31. 31.
    Hardy C. 1996. Characterisation of an essential Orc2p-associated factor that plays a role in DNA replication. Mol. Cell. Biol. 16:1832–41
     [Google Scholar]
  32. 32.
    Ocana-Pallares E, Vergara Z, Desvoyes B, Tejada-Jimenez M, Romero-Jurado A et al. 2020. Origin recognition complex (ORC) evolution is influenced by global gene duplication/loss patterns in eukaryotic genomes. Genome Biol. Evol. 12:3878–89
     [Google Scholar]
  33. 33.
    Siddiqui K, Stillman B. 2007. ATP-dependent assembly of the human origin recognition complex. J. Biol. Chem. 282:32370–83
     [Google Scholar]
  34. 34.
    Vashee S, Simancek P, Challberg MD, Kelly TJ. 2001. Assembly of the human origin recognition complex. J. Biol. Chem. 276:26666–73
     [Google Scholar]
  35. 35.
    Chesnokov I, Gossen M, Remus D, Botchan M 1999. Assembly of functionally active Drosophila origin recognition complex from recombinant proteins. Genes Dev 13:1289–96
     [Google Scholar]
  36. 36.
    Rowles A, Chong JP, Brown L, Howell M, Evan GI, Blow JJ. 1996. Interaction between the origin recognition complex and the replication licensing system in Xenopus. Cell 87:287–96
     [Google Scholar]
  37. 37.
    Chou HC, Bhalla K, Demerdesh OE, Klingbeil O, Hanington K et al. 2021. The human origin recognition complex is essential for pre-RC assembly, mitosis, and maintenance of nuclear structure. eLife 10:e61797
     [Google Scholar]
  38. 38.
    Shibata E, Kiran M, Shibata Y, Singh S, Kiran S, Dutta A 2016. Two subunits of human ORC are dispensable for DNA replication and proliferation. eLife 5:e19084
     [Google Scholar]
  39. 39.
    Eaton ML, Galani K, Kang S, Bell SP, MacAlpine DM. 2010. Conserved nucleosome positioning defines replication origins. Genes Dev 24:748–53
     [Google Scholar]
  40. 40.
    Marahrens Y, Stillman B. 1992. A yeast chromosomal origin of DNA replication defined by multiple functional elements. Science 255:817–23
     [Google Scholar]
  41. 41.
    Lipford JR, Bell SP. 2001. Nucleosomes positioned by ORC facilitate the initiation of DNA replication. Mol. Cell 7:21–30
     [Google Scholar]
  42. 42.
    Rowley A, Cocker JH, Harwood J, Diffley JFX. 1995. Initiation complex assembly at budding yeast replication origins begins with the recognition of a bipartite sequence by limiting amounts of the initiator, ORC. EMBO J 14:2631–41
     [Google Scholar]
  43. 43.
    Rao H, Stillman B. 1995. The origin recognition complex interacts with a bipartite DNA binding site within yeast replicators. PNAS 92:2224–28
     [Google Scholar]
  44. 44.
    Wilmes GM, Bell SP. 2002. The B2 element of the Saccharomyces cerevisiae ARS1 origin of replication requires specific sequences to facilitate pre-RC formation. PNAS 99:101–6
     [Google Scholar]
  45. 45.
    Palzkill TG, Newlon CS. 1988. A yeast replication origin consists of multiple copies of a small conserved sequence. Cell 53:441–50
     [Google Scholar]
  46. 46.
    Umek RM, Kowalski D. 1988. The ease of DNA unwinding as a determinant of initiation at yeast replication origins. Cell 52:559–67
     [Google Scholar]
  47. 47.
    Harland RM, Laskey RA. 1980. Regulated replication of DNA microinjected into eggs of Xenopus laevis. Cell 21:761–71
     [Google Scholar]
  48. 48.
    Prioleau MN, MacAlpine DM. 2016. DNA replication origins—where do we begin?. Genes Dev 30:1683–97
     [Google Scholar]
  49. 49.
    Mechali M, Yoshida K, Coulombe P, Pasero P. 2013. Genetic and epigenetic determinants of DNA replication origins, position and activation. Curr. Opin. Genet. Dev. 23:124–31
     [Google Scholar]
  50. 50.
    Vashee S, Cvetic C, Lu W, Simancek P, Kelly TJ, Walter JC. 2003. Sequence-independent DNA binding and replication initiation by the human origin recognition complex. Genes Dev 17:1894–908
     [Google Scholar]
  51. 51.
    Remus D, Beall EL, Botchan MR. 2004. DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC–DNA binding. EMBO J 23:897–907
     [Google Scholar]
  52. 52.
    Hoshina S, Yura K, Teranishi H, Kiyasu N, Tominaga A et al. 2013. Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA. J. Biol. Chem. 288:30161–71
     [Google Scholar]
  53. 53.
    Kuo AJ, Song J, Cheung P, Ishibe-Murakami S, Yamazoe S et al. 2012. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484:115–19
     [Google Scholar]
  54. 54.
    Iizuka M, Stillman B. 1999. Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. J. Biol. Chem. 274:23027–34
     [Google Scholar]
  55. 55.
    Shen Z, Sathyan KM, Geng Y, Zheng R, Chakraborty A et al. 2010. A WD-repeat protein stabilizes ORC binding to chromatin. Mol. Cell 40:99–111
     [Google Scholar]
  56. 56.
    Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T. 2010. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143:470–84
     [Google Scholar]
  57. 57.
    Bowers JL, Randell JC, Chen S, Bell SP 2004. ATP hydrolysis by ORC catalyzes reiterative Mcm2–7 assembly at a defined origin of replication. Mol. Cell 16:967–78
     [Google Scholar]
  58. 58.
    Chesnokov IN, Chesnokova ON, Botchan M. 2003. A cytokinetic function of Drosophila ORC6 protein resides in a domain distinct from its replication activity. PNAS 100:9150–55
     [Google Scholar]
  59. 59.
    Miller TCR, Locke J, Greiwe JF, Diffley JFX, Costa A 2019. Mechanism of head-to-head MCM double-hexamer formation revealed by cryo-EM. Nature 575:704–10
     [Google Scholar]
  60. 60.
    Bleichert F, Botchan MR, Berger JM. 2015. Crystal structure of the eukaryotic origin recognition complex. Nature 519:321–26
     [Google Scholar]
  61. 61.
    Schmidt JM, Bleichert F. 2020. Structural mechanism for replication origin binding and remodeling by a metazoan origin recognition complex and its co-loader Cdc6. Nat. Commun. 11:4263
     [Google Scholar]
  62. 62.
    Li N, Lam WH, Zhai Y, Cheng J, Cheng E et al. 2018. Structure of the origin recognition complex bound to DNA replication origin. Nature 559:217–22
     [Google Scholar]
  63. 63.
    Jaremko MJ, On KF, Thomas DR, Stillman B, Joshua-Tor L 2020. The dynamic nature of the human origin recognition complex revealed through five cryoEM structures. eLife 9:e58622
     [Google Scholar]
  64. 64.
    Feng X, Noguchi Y, Barbon M, Stillman B, Speck C, Li H. 2021. The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6. Nat. Commun. 12:3883
     [Google Scholar]
  65. 65.
    Gaudier M, Schuwirth BS, Westcott SL, Wigley DB. 2007. Structural basis of DNA replication origin recognition by an ORC protein. Science 317:1213–16
     [Google Scholar]
  66. 66.
    Dueber EL, Corn JE, Bell SD, Berger JM. 2007. Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science 317:1210–13
     [Google Scholar]
  67. 67.
    Hu Y, Tareen A, Sheu YJ, Ireland WT, Speck C et al. 2020. Evolution of DNA replication origin specification and gene silencing mechanisms. Nat. Commun. 11:5175
     [Google Scholar]
  68. 68.
    De Ioannes P, Leon VA, Kuang Z, Wang M, Boeke JD et al. 2019. Structure and function of the Orc1 BAH-nucleosome complex. Nat. Commun. 10:2894
     [Google Scholar]
  69. 69.
    Harland R. 1981. Initiation of DNA replication in eukaryotic chromosomes. Trends Biochem. Sci. 6:71–74
     [Google Scholar]
  70. 70.
    Blow JJ, Laskey RA. 1988. A role for the nuclear envelope in controlling DNA replication within the cell cycle. Nature 332:546–48
     [Google Scholar]
  71. 71.
    Kubota Y, Mimura S, Nishimoto S-I, Takisawa H, Nojima H. 1995. Identification of the yeast MCM3-related protein as a component of Xenopus DNA replication licensing factor. Cell 81:601–9
     [Google Scholar]
  72. 72.
    Chong JPJ, Mahbubani HM, Khoo C-Y, Blow JJ. 1995. Purification of an MCM-containing complex as a component of the DNA replication licensing system. Nature 375:418–21
     [Google Scholar]
  73. 73.
    Madine MA, Khoo CY, Mills AD, Laskey RA. 1995. MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells. Nature 375:421–24
     [Google Scholar]
  74. 74.
    Diffley JFX, Cocker JH, Dowell SJ, Rowley A. 1994. Two steps in the assembly of complexes at yeast replication origins in vivo. Cell 78:303–16
     [Google Scholar]
  75. 75.
    Aparicio OM, Weinstein DM, Bell SP. 1997. Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase. Cell 91:59–69
     [Google Scholar]
  76. 76.
    Tanaka T, Knapp D, Nasmyth K. 1997. Loading of an Mcm protein onto DNA-replication origins is regulated by Cdc6p and CDKs. Cell 90:649–60
     [Google Scholar]
  77. 77.
    Cocker JH, Piatti S, Santocanale C, Nasmyth K, Diffley JFX. 1996. An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast. Nature 379:180–82
     [Google Scholar]
  78. 78.
    Coleman TR, Carpenter PB, Dunphy WG. 1996. The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Cell 87:53–63
     [Google Scholar]
  79. 79.
    Donovan S, Harwood J, Drury LS, Diffley JFX. 1997. Cdc6p-dependent loading of Mcm proteins onto pre-replicative chromatin in budding yeast. PNAS 94:5611–16
     [Google Scholar]
  80. 80.
    Li N, Zhai Y, Zhang Y, Li W, Yang M et al. 2015. Structure of the eukaryotic MCM complex at 3.8 Å. Nature 524:186–91
     [Google Scholar]
  81. 81.
    Zhai Y, Cheng E, Wu H, Li N, Yung PY et al. 2017. Open-ringed structure of the Cdt1–Mcm2–7 complex as a precursor of the MCM double hexamer. Nat. Struct. Mol. Biol. 24:300–8
     [Google Scholar]
  82. 82.
    Frigola J, He J, Kinkelin K, Pye VE, Renault L et al. 2017. Cdt1 stabilizes an open MCM ring for helicase loading. Nat. Commun. 8:15720
     [Google Scholar]
  83. 83.
    Samel SA, Fernandez-Cid A, Sun J, Riera A, Tognetti S et al. 2014. A unique DNA entry gate serves for regulated loading of the eukaryotic replicative helicase MCM2–7 onto DNA. Genes Dev. 28:1653–66
     [Google Scholar]
  84. 84.
    Parker MW, Bell M, Mir M, Kao JA, Darzacq X et al. 2019. A new class of disordered elements controls DNA replication through initiator self-assembly. eLife 8:e48562
     [Google Scholar]
  85. 85.
    Frigola J, Remus D, Mehanna A, Diffley JFX. 2013. ATPase-dependent quality control of DNA replication origin licensing. Nature 495:339–43
     [Google Scholar]
  86. 86.
    Yuan Z, Schneider S, Dodd T, Riera A, Bai L et al. 2020. Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6. PNAS 117:17747–56
     [Google Scholar]
  87. 87.
    Yuan Z, Riera A, Bai L, Sun J, Nandi S et al. 2017. Structural basis of Mcm2–7 replicative helicase loading by ORC-Cdc6 and Cdt1. Nat. Struct. Mol. Biol 24:316–24
     [Google Scholar]
  88. 88.
    Ticau S, Friedman LJ, Champasa K, Correa IR Jr., Gelles J, Bell SP. 2017. Mechanism and timing of Mcm2–7 ring closure during DNA replication origin licensing. Nat. Struct. Mol. Biol. 24:309–15
     [Google Scholar]
  89. 89.
    Ticau S, Friedman LJ, Ivica NA, Gelles J, Bell SP. 2015. Single-molecule studies of origin licensing reveal mechanisms ensuring bidirectional helicase loading. Cell 161:513–25
     [Google Scholar]
  90. 90.
    Coster G, Frigola J, Beuron F, Morris EP, Diffley JFX. 2014. Origin licensing requires ATP binding and hydrolysis by the MCM replicative helicase. Mol. Cell 55:666–77
     [Google Scholar]
  91. 91.
    Kang S, Warner MD, Bell SP. 2014. Multiple functions for Mcm2–7 ATPase motifs during replication initiation. Mol. Cell 55:655–65
     [Google Scholar]
  92. 92.
    Frigola J, Remus D, Mehanna A, Diffley JFX. 2013. ATPase-dependent quality control of DNA replication origin licensing. Nature 495:339–43
     [Google Scholar]
  93. 93.
    Sanchez H, McCluskey K, van Laar T, van Veen E, Asscher FM et al. 2021. DNA replication origins retain mobile licensing proteins. Nat. Commun. 12:1908
     [Google Scholar]
  94. 94.
    Noguchi K, Vassilev A, Ghosh S, Yates JL, DePamphilis ML. 2006. The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J 25:5372–82
     [Google Scholar]
  95. 95.
    Abid Ali F, Douglas ME, Locke J, Pye VE, Nans A et al. 2017. Cryo-EM structure of a licensed DNA replication origin. Nat. Commun. 8:2241
     [Google Scholar]
  96. 96.
    Dahmann C, Diffley JFX, Nasmyth KA. 1995. S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition of replication origins to a pre-replicative state. Curr. Biol. 5:1257–69
     [Google Scholar]
  97. 97.
    Noton E, Diffley JFX. 2000. CDK inactivation is the only essential function of the APC/C and the mitotic exit network proteins for origin resetting during mitosis. Mol. Cell 5:85–95
     [Google Scholar]
  98. 98.
    Drury LS, Perkins G, Diffley JFX. 1997. The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast. EMBO J 16:5966–76
     [Google Scholar]
  99. 99.
    Drury LS, Perkins G, Diffley JFX. 2000. The cyclin-dependent kinase Cdc28p regulates distinct modes of Cdc6p proteolysis during the budding yeast cell cycle. Curr. Biol. 10:231–40
     [Google Scholar]
  100. 100.
    Elsasser S, Chi Y, Yang P, Campbell JL 1999. Phosphorylation controls timing of Cdc6p destruction: a biochemical analysis. Mol. Biol. Cell 10:3263–77
     [Google Scholar]
  101. 101.
    Perkins G, Drury LS, Diffley JFX. 2001. Separate SCFCDC4 recognition elements target Cdc6 for proteolysis in S phase and mitosis. EMBO J 20:4836–45
     [Google Scholar]
  102. 102.
    Piatti S, Bohm T, Cocker JH, Diffley JFX, Nasmyth K. 1996. Activation of S-phase-promoting CDKs in late G1 defines a “point of no return” after which Cdc6 synthesis cannot promote DNA replication in yeast. Genes Dev. 10:1516–31
     [Google Scholar]
  103. 103.
    Labib K, Diffley JFX, Kearsey SE. 1999. G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nat. Cell Biol. 1:415–22
     [Google Scholar]
  104. 104.
    Nguyen VQ, Co C, Irie K, Li JJ. 2000. Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins Mcm2–7. Curr. Biol. 10:195–205
     [Google Scholar]
  105. 105.
    Liku ME, Nguyen VQ, Rosales AW, Irie K, Li JJ. 2005. CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2–7 complex prevents chromosomal rereplication. Mol. Biol. Cell 16:5026–39
     [Google Scholar]
  106. 106.
    Tanaka S, Diffley JFX. 2002. Interdependent nuclear accumulation of budding yeast Cdt1 and Mcm2–7 during G1 phase. Nat. Cell Biol. 4:198–207
     [Google Scholar]
  107. 107.
    Hennessy KM, Clark CD, Botstein D. 1990. Subcellular localization of yeast CDC46 varies with the cell cycle. Genes Dev. 4:2252–63
     [Google Scholar]
  108. 108.
    Chen S, Bell SP. 2011. CDK prevents Mcm2–7 helicase loading by inhibiting Cdt1 interaction with Orc6. Genes Dev. 25:363–72
     [Google Scholar]
  109. 109.
    Wilmes GM, Archambault V, Austin RJ, Jacobson MD, Bell SP, Cross FR. 2004. Interaction of the S-phase cyclin Clb5 with an ‘RXL’ docking sequence in the initiator protein Orc6 provides an origin-localized replication control switch. Genes Dev. 18:981–91
     [Google Scholar]
  110. 110.
    Nguyen VQ, Co C, Li JJ. 2001. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature 411:1068–73
     [Google Scholar]
  111. 111.
    Drury LS, Diffley JFX. 2009. Factors affecting the diversity of DNA replication licensing control in eukaryotes. Curr. Biol. 19:530–35
     [Google Scholar]
  112. 112.
    McGarry TJ, Kirschner MW. 1998. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93:1043–53
     [Google Scholar]
  113. 113.
    Arias EE, Walter JC. 2005. Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. Genes Dev 19:114–26
     [Google Scholar]
  114. 114.
    Takeda DY, Parvin JD, Dutta A. 2005. Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase. J. Biol. Chem. 280:23416–23
     [Google Scholar]
  115. 115.
    Mendez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B. 2002. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol. Cell 9:481–91
     [Google Scholar]
  116. 116.
    Araki H. 2011. Initiation of chromosomal DNA replication in eukaryotic cells; contribution of yeast genetics to the elucidation. Genes Genet. Syst. 86:141–49
     [Google Scholar]
  117. 117.
    Burgers PMJ, Kunkel TA. 2017. Eukaryotic DNA replication fork. Annu. Rev. Biochem. 86:417–38
     [Google Scholar]
  118. 118.
    Labib K. 2010. How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells?. Genes Dev 24:1208–19
     [Google Scholar]
  119. 119.
    Zou L, 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. 20:3086–96
     [Google Scholar]
  120. 120.
    Deegan TD, Yeeles JT, Diffley JFX. 2016. Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. EMBO J 35:961–73
     [Google Scholar]
  121. 121.
    Randell JC, Fan A, Chan C, Francis LI, Heller RC et al. 2010. Mec1 is one of multiple kinases that prime the Mcm2–7 helicase for phosphorylation by Cdc7. Mol. Cell 40:353–63
     [Google Scholar]
  122. 122.
    Hardy CF, Dryga O, Seematter S, Pahl PM, Sclafani RA 1997. Mcm5/Cdc46-bob1 bypasses the requirement for the S phase activator Cdc7p. PNAS 94:3151–55
     [Google Scholar]
  123. 123.
    Sheu YJ, Stillman B. 2010. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature 463:113–17
     [Google Scholar]
  124. 124.
    Francis LI, Randell JC, Takara TJ, Uchima L, Bell SP. 2009. Incorporation into the prereplicative complex activates the Mcm2–7 helicase for Cdc7-Dbf4 phosphorylation. Genes Dev. 23:643–54
     [Google Scholar]
  125. 125.
    Tanaka S, Nakato R, Katou Y, Shirahige K, Araki H. 2011. Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr. Biol. 21:2055–63
     [Google Scholar]
  126. 126.
    Tanaka S, Umemori T, Hirai K, Muramatsu S, Kamimura Y, Araki H. 2007. CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature 445:328–32
     [Google Scholar]
  127. 127.
    Masumoto H, Muramatsu S, Kamimura Y, Araki H. 2002. S-Cdk-dependent phosphorylation of Sld2 essential for chromosomal DNA replication in budding yeast. Nature 415:651–65
     [Google Scholar]
  128. 128.
    Zegerman P, Diffley JFX. 2007. Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature 445:281–85
     [Google Scholar]
  129. 129.
    Tak YS, Tanaka Y, Endo S, Kamimura Y, Araki H. 2006. A CDK-catalysed regulatory phosphorylation for formation of the DNA replication complex Sld2-Dpb11. EMBO J 25:1987–96
     [Google Scholar]
  130. 130.
    Kumagai A, Shevchenko A, Dunphy WG. 2010. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication. Cell 140:349–59
     [Google Scholar]
  131. 131.
    Kumagai A, Shevchenko A, Dunphy WG. 2011. Direct regulation of Treslin by cyclin-dependent kinase is essential for the onset of DNA replication. J. Cell Biol. 193:995–1007
     [Google Scholar]
  132. 132.
    Sansam CL, Cruz NM, Danielian PS, Amsterdam A, Lau ML et al. 2010. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator. Genes Dev 24:183–94
     [Google Scholar]
  133. 133.
    Boos D, Sanchez-Pulido L, Rappas M, Pearl LH, Oliver AW et al. 2011. Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Curr. Biol. 21:1152–57
     [Google Scholar]
  134. 134.
    Sanchez-Pulido L, Diffley JFX, Ponting CP. 2010. Homology explains the functional similarities of Treslin/Ticrr and Sld3. Curr. Biol. 20:R509–10
     [Google Scholar]
  135. 135.
    Muramatsu S, Hirai K, Tak YS, Kamimura Y, Araki H. 2010. CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol ε, and GINS in budding yeast. Genes Dev. 24:602–12
     [Google Scholar]
  136. 136.
    Mantiero D, Mackenzie A, Donaldson A, Zegerman P. 2011. Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J. 30:4805–14
     [Google Scholar]
  137. 137.
    Douglas ME, Diffley JFX. 2012. Replication timing: The early bird catches the worm. Curr. Biol. 22:R81–82
     [Google Scholar]
  138. 138.
    Santocanale C, Diffley JFX. 1998. A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395:615–18
     [Google Scholar]
  139. 139.
    Shirahige K, Hori Y, Shiraishi K, Yamashita M, Takahashi K et al. 1998. Regulation of DNA-replication origins during cell-cycle progression. Nature 395:618–21
     [Google Scholar]
  140. 140.
    Lopez-Mosqueda J, Maas NL, Jonsson ZO, Defazio-Eli LG, Wohlschlegel J, Toczyski DP. 2010. Damage-induced phosphorylation of Sld3 is important to block late origin firing. Nature 467:479–83
     [Google Scholar]
  141. 141.
    Zegerman P, Diffley JFX. 2010. Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. Nature 467:474–78
     [Google Scholar]
  142. 142.
    Douglas ME, Ali FA, Costa A, Diffley JFX 2018. The mechanism of eukaryotic CMG helicase activation. Nature 555:265–68
     [Google Scholar]
  143. 143.
    Georgescu R, Yuan Z, Bai L, de Luna Almeida Santos R, Sun J et al. 2017. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. PNAS 114:E697–706
     [Google Scholar]
  144. 144.
    Gros J, Kumar C, Lynch G, Yadav T, Whitehouse I, Remus D 2015. Post-licensing specification of eukaryotic replication origins by facilitated Mcm2–7 sliding along DNA. Mol. Cell 60:797–807
     [Google Scholar]
  145. 145.
    Sinha P, Chang V, Tye BK 1986. A mutant that affects the function of autonomously replicating sequences in yeast. J. Mol. Biol. 192:805–14
     [Google Scholar]
  146. 146.
    Labib K, Tercero JA, Diffley JFX. 2000. Uninterrupted MCM2–7 function required for DNA replication fork progression. Science 288:1643–47
     [Google Scholar]
  147. 147.
    Tercero JA, Labib K, Diffley JFX. 2000. DNA synthesis at individual replication forks requires the essential initiation factor Cdc45p. EMBO J 19:2082–93
     [Google Scholar]
  148. 148.
    Ishimi Y. 1997. A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J. Biol. Chem. 272:24508–13
     [Google Scholar]
  149. 149.
    Bochman ML, Schwacha A. 2008. The Mcm2–7 complex has in vitro helicase activity. Mol Cell 31:287–93
     [Google Scholar]
  150. 150.
    Costa A, Ilves I, Tamberg N, Petojevic T, Nogales E et al. 2011. The structural basis for MCM2–7 helicase activation by GINS and Cdc45. Nat. Struct. Mol. Biol. 18:471–77
     [Google Scholar]
  151. 151.
    Ilves I, Petojevic T, Pesavento JJ, Botchan MR. 2010. Activation of the MCM2–7 helicase by association with Cdc45 and GINS proteins. Mol. Cell 37:247–58
     [Google Scholar]
  152. 152.
    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. PNAS 103:10236–41
     [Google Scholar]
  153. 153.
    Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F et al. 2006. GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat. Cell Biol. 8:358–66
     [Google Scholar]
  154. 154.
    Deegan TD, Diffley JFX. 2016. MCM: one ring to rule them all. Curr. Opin. Struct. Biol. 37:145–51
     [Google Scholar]
  155. 155.
    Sheu YJ, Stillman B. 2006. Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol. Cell 24:101–13
     [Google Scholar]
  156. 156.
    Itou H, Shirakihara Y, Araki H. 2015. The quaternary structure of the eukaryotic DNA replication proteins Sld7 and Sld3. Acta Crystallogr. D Biol. Crystallogr. 71:1649–56
     [Google Scholar]
  157. 157.
    De Jesus-Kim L, Friedman LJ, Looke M, Ramsoomair CK, Gelles J, Bell SP 2021. DDK regulates replication initiation by controlling the multiplicity of Cdc45-GINS binding to Mcm2–7. eLife 10:e65471
     [Google Scholar]
  158. 158.
    Champasa K, Blank C, Friedman LJ, Gelles J, Bell SP 2019. A conserved Mcm4 motif is required for Mcm2–7 double-hexamer formation and origin DNA unwinding. eLife 8:e45538
     [Google Scholar]
  159. 159.
    Abid Ali F, Renault L, Gannon J, Gahlon HL, Kotecha A et al. 2016. Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate. Nat. Commun. 7:10708
     [Google Scholar]
  160. 160.
    Yuan Z, Bai L, Sun J, Georgescu R, Liu J et al. 2016. Structure of the eukaryotic replicative CMG helicase suggests a pumpjack motion for translocation. Nat. Struct. Mol. Biol. 23:217–24
     [Google Scholar]
  161. 161.
    Eickhoff P, Kose HB, Martino F, Petojevic T, Abid Ali F et al. 2019. Molecular basis for ATP-hydrolysis-driven DNA translocation by the CMG helicase of the eukaryotic replisome. Cell Rep 28:2673–88.e8
     [Google Scholar]
  162. 162.
    Yuan Z, Georgescu R, Bai L, Zhang D, Li H, O'Donnell ME. 2020. DNA unwinding mechanism of a eukaryotic replicative CMG helicase. Nat. Commun. 11:688
     [Google Scholar]
  163. 163.
    Baretic D, Jenkyn-Bedford M, Aria V, Cannone G, Skehel M, Yeeles JTP. 2020. Cryo-EM structure of the fork protection complex bound to CMG at a replication fork. Mol. Cell 78:926–40.e13
     [Google Scholar]
  164. 164.
    Goswami P, Abid Ali F, Douglas ME, Locke J, Purkiss A et al. 2018. Structure of DNA-CMG-Pol epsilon elucidates the roles of the non-catalytic polymerase modules in the eukaryotic replisome. Nat. Commun. 9:5061
     [Google Scholar]
  165. 165.
    Langston LD, Mayle R, Schauer GD, Yurieva O, Zhang D et al. 2017. Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks. eLife 6:e29118
     [Google Scholar]
  166. 166.
    Kose HB, Larsen NB, Duxin JP, Yardimci H. 2019. Dynamics of the eukaryotic replicative helicase at lagging-strand protein barriers support the steric exclusion model. Cell Rep 26:2113–25.e6
     [Google Scholar]
  167. 167.
    Kose HB, Xie S, Cameron G, Strycharska MS, Yardimci H. 2020. Duplex DNA engagement and RPA oppositely regulate the DNA-unwinding rate of CMG helicase. Nat. Commun. 11:3713
     [Google Scholar]
  168. 168.
    Kang YH, Farina A, Bermudez VP, Tappin I, Du F et al. 2013. Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase. PNAS 110:19760–65
     [Google Scholar]
  169. 169.
    Yeeles JTP, Deegan TD, Janska A, Early A, Diffley JFX. 2015. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 519:431–35
     [Google Scholar]
  170. 170.
    Georgescu RE, Langston L, Yao NY, Yurieva O, Zhang D et al. 2014. Mechanism of asymmetric polymerase assembly at the eukaryotic replication fork. Nat. Struct. Mol. Biol. 21:664–70
     [Google Scholar]
  171. 171.
    Langston LD, Zhang D, Yurieva O, Georgescu RE, Finkelstein J et al. 2014. CMG helicase and DNA polymerase ε form a functional 15-subunit holoenzyme for eukaryotic leading-strand DNA replication. PNAS 111:15390–95
     [Google Scholar]
  172. 172.
    Kesti T, Flick K, Keränen S, Syväoja JE, Wittenberg C. 1999. DNA polymerase ε catalytic domains are dispensable for DNA replication, DNA repair, and cell viability. Mol. Cell 3:679–85
     [Google Scholar]
  173. 173.
    Dua R, Levy DL, Campbell JL. 1998. Role of the putative zinc finger domain of Saccharomyces cerevisiae DNA polymerase ε in DNA replication and the S/M checkpoint pathway. J. Biol. Chem. 273:30046–55
     [Google Scholar]
  174. 174.
    Sengupta S, van Deursen F, de Piccoli G, Labib K. 2013. Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome. Curr. Biol. 23:543–52
     [Google Scholar]
  175. 175.
    Looke M, Maloney MF, Bell SP. 2017. Mcm10 regulates DNA replication elongation by stimulating the CMG replicative helicase. Genes Dev 31:291–305
     [Google Scholar]
  176. 176.
    Wasserman MR, Schauer GD, ME O'Donnell, Liu S. 2019. Replication fork activation is enabled by a single-stranded DNA gate in CMG helicase. Cell 178:600–11.e16
     [Google Scholar]
  177. 177.
    Lewis JS, Spenkelink LM, Schauer GD, Hill FR, Georgescu RE et al. 2017. Single-molecule visualization of Saccharomyces cerevisiae leading-strand synthesis reveals dynamic interaction between MTC and the replisome. PNAS 114:10630–35
     [Google Scholar]
  178. 178.
    Yeeles JT, Janska A, Early A, Diffley JFX. 2017. How the eukaryotic replisome achieves rapid and efficient DNA replication. Mol. Cell 65:105–16
     [Google Scholar]
  179. 179.
    Puchades C, Sandate CR, Lander GC. 2020. The molecular principles governing the activity and functional diversity of AAA+ proteins. Nat. Rev. Mol. Cell Biol. 21:43–58
     [Google Scholar]
  180. 180.
    Thomsen ND, Berger JM. 2009. Running in reverse: the structural basis for translocation polarity in hexameric helicases. Cell 139:523–34
     [Google Scholar]
  181. 181.
    Enemark EJ, Joshua-Tor L. 2006. Mechanism of DNA translocation in a replicative hexameric helicase. Nature 442:270–75
     [Google Scholar]
  182. 182.
    Meagher M, Epling LB, Enemark EJ. 2019. DNA translocation mechanism of the MCM complex and implications for replication initiation. Nat. Commun. 10:3117
     [Google Scholar]
  183. 183.
    Gao Y, Cui Y, Fox T, Lin S, Wang H et al. 2019. Structures and operating principles of the replisome. Science 363:eaav7003
     [Google Scholar]
  184. 184.
    Attali I, Botchan MR, Berger JM. 2021. Structural mechanisms for replicating DNA in eukaryotes. Annu. Rev. Biochem. 90:77–106
     [Google Scholar]
  185. 185.
    Simon AC, Zhou JC, Perera RL, van Deursen F, Evrin C et al. 2014. A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome. Nature 510:293–97
     [Google Scholar]
  186. 186.
    Villa F, Simon AC, Ortiz Bazan MA, Kilkenny ML, Wirthensohn D et al. 2016. Ctf4 is a hub in the eukaryotic replisome that links multiple CIP-box proteins to the CMG helicase. Mol. Cell 63:385–96
     [Google Scholar]
  187. 187.
    Samora CP, Saksouk J, Goswami P, Wade BO, Singleton MR et al. 2016. Ctf4 links DNA replication with sister chromatid cohesion establishment by recruiting the Chl1 helicase to the replisome. Mol. Cell 63:371–84
     [Google Scholar]
  188. 188.
    Yuan Z, Georgescu R, Santos RLA, Zhang D, Bai L et al. 2019. Ctf4 organizes sister replisomes and Pol α into a replication factory. eLife 8:e47405
     [Google Scholar]
  189. 189.
    Lewis JS, Spenkelink LM, Schauer GD, Yurieva O, Mueller SH et al. 2020. Tunability of DNA polymerase stability during eukaryotic DNA replication. Mol. Cell 77:17–25.e5
     [Google Scholar]
  190. 190.
    Yardimci H, Loveland AB, Habuchi S, van Oijen AM, Walter JC. 2010. Uncoupling of sister replisomes during eukaryotic DNA replication. Mol. Cell 40:834–40
     [Google Scholar]
  191. 191.
    Petronczki M, Chwalla B, Siomos MF, Yokobayashi S, Helmhart W et al. 2004. Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-α-associated protein Ctf4 is essential for chromatid disjunction during meiosis II. J. Cell Sci. 117:3547–59
     [Google Scholar]
  192. 192.
    Gan H, Serra-Cardona A, Hua X, Zhou H, Labib K et al. 2018. The Mcm2-Ctf4-Polα axis facilitates parental histone H3-H4 transfer to lagging strands. Mol. Cell 72:140–51.e3
     [Google Scholar]
  193. 193.
    Hogg M, Osterman P, Bylund GO, Ganai RA, Lundstrom EB et al. 2014. Structural basis for processive DNA synthesis by yeast DNA polymerase ε. Nat. Struct. Mol. Biol. 21:49–55
     [Google Scholar]
  194. 194.
    Lancey C, Tehseen M, Raducanu VS, Rashid F, Merino N et al. 2020. Structure of the processive human Pol δ holoenzyme. Nat. Commun. 11:1109
     [Google Scholar]
  195. 195.
    Zhou JC, Janska A, Goswami P, Renault L, Abid Ali F et al. 2017. CMG–Pol epsilon dynamics suggests a mechanism for the establishment of leading-strand synthesis in the eukaryotic replisome. PNAS 114:4141–46
     [Google Scholar]
  196. 196.
    Yuan Z, Georgescu R, Schauer GD, O'Donnell ME, Li H. 2020. Structure of the polymerase ε holoenzyme and atomic model of the leading strand replisome. Nat. Commun. 11:3156
     [Google Scholar]
  197. 197.
    Johansson E, Garg P, Burgers PM. 2004. The Pol32 subunit of DNA polymerase delta contains separable domains for processive replication and proliferating cell nuclear antigen (PCNA) binding. J. Biol. Chem. 279:1907–15
     [Google Scholar]
/content/journals/10.1146/annurev-biochem-072321-110228
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The Initiation of Eukaryotic DNA Replication
Annual Review of Biochemistry 91, 107 (2022); https://doi.org/10.1146/annurev-biochem-072321-110228
/content/journals/10.1146/annurev-biochem-072321-110228
/content/journals/10.1146/annurev-biochem-072321-110228
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