1932

Abstract

This review focuses on the biogenesis and composition of the eukaryotic DNA replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork. Physical and genetic methodologies aimed at understanding these processes are discussed. The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork. DNA polymerases α and δ carry out the initiation of Okazaki fragment synthesis and its elongation and maturation, respectively. This review also discusses alternative proposals, including cellular processes during which alternative forks may be utilized, and new biochemical studies with purified proteins that are aimed at reconstituting leading and lagging strand DNA synthesis separately and as an integrated replication fork.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-061516-044709
2017-06-20
2024-04-14
Loading full text...

Full text loading...

/deliver/fulltext/biochem/86/1/annurev-biochem-061516-044709.html?itemId=/content/journals/10.1146/annurev-biochem-061516-044709&mimeType=html&fmt=ahah

Literature Cited

  1. Watson JD, Crick FH. 1.  1953. Genetical implications of the structure of deoxyribonucleic acid. Nature 171:964–67 [Google Scholar]
  2. Okazaki R, Okazaki T, Sakabe K, Sugimoto K, Kainuma R. 2.  et al. 1968. In vivo mechanism of DNA chain growth. Cold Spring Harb. Symp. Quant. Biol. 33:129–43 [Google Scholar]
  3. Tye BK, Nyman PO, Lehman IR, Hochhauser S, Weiss B. 3.  1977. Transient accumulation of Okazaki fragments as a result of uracil incorporation into nascent DNA. PNAS 74:154–57 [Google Scholar]
  4. Nick McElhinny SA, Watts BE, Kumar D, Watt DL, Lundstrom EB. 4.  et al. 2010. Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. PNAS 107:4949–54 [Google Scholar]
  5. Yeeles JT, Deegan TD, Janska A, Early A, Diffley JF. 5.  2015. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 519:431–35 [Google Scholar]
  6. Stillman B. 6.  2015. Reconsidering DNA polymerases at the replication fork in eukaryotes. Mol. Cell 59:139–41 [Google Scholar]
  7. Masai H, Matsumoto S, You Z, Yoshizawa-Sugata N, Oda M. 7.  2010. Eukaryotic chromosome DNA replication: where, when, and how?. Annu. Rev. Biochem. 79:89–130 [Google Scholar]
  8. Costa A, Hood IV, Berger JM. 8.  2013. Mechanisms for initiating cellular DNA replication. Annu. Rev. Biochem. 82:25–54 [Google Scholar]
  9. Bell SP, Labib K. 9.  2016. Chromosome duplication in Saccharomycescerevisiae. Genetics 203:1027–67 [Google Scholar]
  10. Deegan TD, Diffley JF. 10.  2016. MCM: one ring to rule them all. Curr. Opin. Struct. Biol. 37:145–51 [Google Scholar]
  11. Ticau S, Friedman LJ, Ivica NA, Gelles J, Bell SP. 11.  2015. Single-molecule studies of origin licensing reveal mechanisms ensuring bidirectional helicase loading. Cell 161:513–25 [Google Scholar]
  12. Takayama Y, Kamimura Y, Okawa M, Muramatsu S, Sugino A, Araki H. 12.  2003. GINS, a novel multiprotein complex required for chromosomal DNA replication in budding yeast. Genes Dev 17:1153–65 [Google Scholar]
  13. Muramatsu S, Hirai K, Tak YS, Kamimura Y, Araki H. 13.  2010. CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol ε, and GINS in budding yeast. Genes Dev 24:602–12 [Google Scholar]
  14. Sengupta S, van Deursen F, de Piccoli G, Labib K. 14.  2013. Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome. Curr. Biol. 23:543–52 [Google Scholar]
  15. Heller RC, Kang S, Lam WM, Chen S, Chan CS, Bell SP. 15.  2011. Eukaryotic origin-dependent DNA replication in vitro reveals sequential action of DDK and S-CDK kinases. Cell 146:80–91 [Google Scholar]
  16. Kanke M, Kodama Y, Takahashi TS, Nakagawa T, Masukata H. 16.  2012. Mcm10 plays an essential role in origin DNA unwinding after loading of the CMG components. EMBO J 31:2182–94 [Google Scholar]
  17. van Deursen F, Sengupta S, De Piccoli G, Sanchez-Diaz A, Labib K. 17.  2012. Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation. EMBO J 31:2195–206 [Google Scholar]
  18. Quan Y, Xia Y, Liu L, Cui J, Li Z. 18.  et al. 2015. Cell-cycle-regulated interaction between Mcm10 and double hexameric Mcm2-7 is required for helicase splitting and activation during S phase. Cell Rep 13:2576–86 [Google Scholar]
  19. Perez-Arnaiz P, Bruck I, Kaplan DL. 19.  2016. Mcm10 coordinates the timely assembly and activation of the replication fork helicase. Nucleic Acids Res 44:315–29 [Google Scholar]
  20. Moyer SE, Lewis PW, Botchan MR. 20.  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]
  21. Pacek M, Tutter AV, Kubota Y, Takisawa H, Walter JC. 21.  2006. Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol. Cell 21:581–87 [Google Scholar]
  22. Sirbu BM, Couch FB, Feigerle JT, Bhaskara S, Hiebert SW, Cortez D. 22.  2011. Analysis of protein dynamics at active, stalled, and collapsed replication forks. Genes Dev 25:1320–27 [Google Scholar]
  23. Yu C, Gan H, Han J, Zhou ZX, Jia S. 23.  et al. 2014. Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. Mol. Cell 56:551–63 [Google Scholar]
  24. Johnson RE, Klassen R, Prakash L, Prakash S. 24.  2015. A major role of DNA polymerase δ in replication of both the leading and lagging DNA strands. Mol. Cell 59:163–75 [Google Scholar]
  25. Joyce CM. 25.  1997. Choosing the right sugar: how polymerases select a nucleotide substrate. PNAS 94:1619–22 [Google Scholar]
  26. Roettger MP, Fiala KA, Sompalli S, Dong Y, Suo Z. 26.  2004. Pre-steady-state kinetic studies of the fidelity of human DNA polymerase μ.. Biochemistry 43:13827–38 [Google Scholar]
  27. Brown JA, Suo Z. 27.  2011. Unlocking the sugar “steric gate” of DNA polymerases. Biochemistry 50:1135–42 [Google Scholar]
  28. Traut TW. 28.  1994. Physiological concentrations of purines and pyrimidines. Mol. Cell Biochem. 140:1–22 [Google Scholar]
  29. Chabes A, Georgieva B, Domkin V, Zhao X, Rothstein R, Thelander L. 29.  2003. Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell 112:391–401 [Google Scholar]
  30. Clausen AR, Zhang S, Burgers PM, Lee MY, Kunkel TA. 30.  2012. Ribonucleotide incorporation, proofreading and bypass by human DNA polymerase δ.. DNA Repair 12:121–27 [Google Scholar]
  31. Goksenin AY, Zahurancik W, LeCompte KG, Taggart DJ, Suo Z, Pursell ZF. 31.  2012. Human DNA polymerase ε is able to efficiently extend from multiple consecutive ribonucleotides. J. Biol. Chem. 287:42675–84 [Google Scholar]
  32. Eder PS, Walder JA. 32.  1991. Ribonuclease H from K562 human erythroleukemia cells. Purification, characterization, and substrate specificity. J. Biol. Chem. 266:6472–79 [Google Scholar]
  33. Rydberg B, Game J. 33.  2002. Excision of misincorporated ribonucleotides in DNA by RNase H (type 2) and FEN-1 in cell-free extracts. PNAS 99:16654–59 [Google Scholar]
  34. Sparks JL, Chon H, Cerritelli SM, Kunkel TA, Johansson E. 34.  et al. 2012. RNase H2-initiated ribonucleotide excision repair. Mol. Cell 47:980–86 [Google Scholar]
  35. Nick McElhinny SA, Kumar D, Clark AB, Watt DL, Watts BE. 35.  et al. 2010. Genome instability due to ribonucleotide incorporation into DNA. Nat. Chem. Biol. 6:774–81 [Google Scholar]
  36. Miyabe I, Kunkel TA, Carr AM. 36.  2011. The major roles of DNA polymerases ε and δ at the eukaryotic replication fork are evolutionarily conserved. PLOS Genet 7:e1002407 [Google Scholar]
  37. Lujan SA, Williams JS, Clausen AR, Clark AB, Kunkel TA. 37.  2014. Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol. Cell 50:437–43 [Google Scholar]
  38. Reijns MAM, Kemp H, Ding J, de Procé SM, Jackson AP, Taylor MS. 38.  2015. Lagging-strand replication shapes the mutational landscape of the genome. Nature 518:502–6 [Google Scholar]
  39. Clausen AR, Lujan SA, Burkholder AB, Orebaugh CD, Williams JS. 39.  et al. 2015. Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat. Struct. Mol. Biol. 22:185–91 [Google Scholar]
  40. Koh KD, Balachander S, Hesselberth JR, Storici F. 40.  2015. Ribose-seq: global mapping of ribonucleotides embedded in genomic DNA. Nat. Methods 12:251–57 [Google Scholar]
  41. Daigaku Y, Keszthelyi A, Muller CA, Miyabe I, Brooks T. 41.  et al. 2015. A global profile of replicative polymerase usage. Nat. Struct. Mol. Biol. 22:192–98 [Google Scholar]
  42. Miyabe I, Mizuno K, Keszthelyi A, Daigaku Y, Skouteri M. 42.  et al. 2015. Polymerase δ replicates both strands after homologous recombination-dependent fork restart. Nat. Struct. Mol. Biol. 22:932–38 [Google Scholar]
  43. Ghodgaonkar MM, Lazzaro F, Olivera-Pimentel M, Artola-Boran M, Cejka P. 43.  et al. 2014. Ribonucleotides misincorporated into DNA act as strand-discrimination signals in eukaryotic mismatch repair. Mol. Cell 50:323–32 [Google Scholar]
  44. Vengrova S, Dalgaard JZ. 44.  2006. The wild-type Schizosaccharomycespombe mat1 imprint consists of two ribonucleotides. EMBO Rep 7:59–65 [Google Scholar]
  45. Kim N, Huang SN, Williams JS, Li YC, Clark AB. 45.  et al. 2011. Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332:1561–64 [Google Scholar]
  46. Williams JS, Clausen AR, Lujan SA, Marjavaara L, Clark AB. 46.  et al. 2015. Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific. Nat. Struct. Mol. Biol. 22:291–97 [Google Scholar]
  47. Reijns MA, Rabe B, Rigby RE, Mill P, Astell KR. 47.  et al. 2012. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–22 [Google Scholar]
  48. Allen-Soltero S, Martinez SL, Putnam CD, Kolodner RD. 48.  2014. A Saccharomycescerevisiae RNase H2 interaction network functions to suppress genome instability. Mol. Cell. Biol. 34:1521–34 [Google Scholar]
  49. Conover HN, Lujan SA, Chapman MJ, Cornelio DA, Sharif R. 49.  et al. 2015. Stimulation of chromosomal rearrangements by ribonucleotides. Genetics 201:951–61 [Google Scholar]
  50. Williams JS, Kunkel TA. 50.  2014. Ribonucleotides in DNA: origins, repair and consequences. DNA Repair 19:27–37 [Google Scholar]
  51. Potenski CJ, Klein HL. 51.  2014. How the misincorporation of ribonucleotides into genomic DNA can be both harmful and helpful to cells. Nucleic Acids Res 42:10226–34 [Google Scholar]
  52. Cerritelli SM, Crouch RJ. 52.  2016. The balancing act of ribonucleotides in DNA. Trends Biochem. Sci. 41:434–45 [Google Scholar]
  53. Williams JS, Lujan SA, Kunkel TA. 53.  2016. Processing ribonucleotides incorporated during eukaryotic DNA replication. Nat. Rev. Mol. Cell Biol. 17:350–63 [Google Scholar]
  54. Morrison A, Araki H, Clark AB, Hamatake RK, Sugino A. 54.  1990. A third essential DNA polymerase in S.cerevisiae. Cell 62:1143–51 [Google Scholar]
  55. Kesti T, Flick K, Keranen S, Syvaoja JE, Wittenberg C. 55.  1999. DNA polymerase ε catalytic domains are dispensable for DNA replication, DNA repair, and cell viability. Mol. Cell 3:679–85 [Google Scholar]
  56. Dua R, Levy DL, Campbell JL. 56.  1999. Analysis of the essential functions of the C-terminal protein/protein interaction domain of Saccharomycescerevisiae pol ε and its unexpected ability to support growth in the absence of the DNA polymerase domain. J. Biol. Chem. 274:22283–88 [Google Scholar]
  57. Feng W, D'Urso G. 57.  2001. Schizosaccharomycespombe cells lacking the amino-terminal catalytic domains of DNA polymerase ε are viable but require the DNA damage checkpoint control. Mol. Cell. Biol. 21:4495–504 [Google Scholar]
  58. Ohya T, Kawasaki Y, Hiraga S, Kanbara S, Nakajo K. 58.  et al. 2002. The DNA polymerase domain of Pol ε is required for rapid, efficient, and highly accurate chromosomal DNA replication, telomere length maintenance, and normal cell senescence in Saccharomycescerevisiae. J. Biol. Chem. 277:28099–108 [Google Scholar]
  59. Pavlov YI, Shcherbakova PV, Kunkel TA. 59.  2001. In vivo consequences of putative active site mutations in yeast DNA polymerases α, ε, δ, and ζ.. Genetics 159:47–64 [Google Scholar]
  60. McElhinny SA, Stith CM, Burgers PM, Kunkel TA. 60.  2007. Inefficient proofreading and biased error rates during inaccurate DNA synthesis by a mutant derivative of Saccharomycescerevisiae DNA polymerase δ.. J. Biol. Chem. 282:2324–32 [Google Scholar]
  61. Nick McElhinny SA, Gordenin DA, Stith CM, Burgers PM, Kunkel TA. 61.  2008. Division of labor at the eukaryotic replication fork. Mol. Cell 30:137–44 [Google Scholar]
  62. Nick McElhinny SA, Kissling GE, Kunkel TA. 62.  2010. Differential correction of lagging-strand replication errors made by DNA polymerases α and δ.. PNAS 107:21070–75 [Google Scholar]
  63. Pursell ZF, Isoz I, Lundstrom EB, Johansson E, Kunkel TA. 63.  2007. Yeast DNA polymerase ε participates in leading-strand DNA replication. Science 317:127–30 [Google Scholar]
  64. Lujan SA, Williams JS, Pursell ZF, Abdulovic-Cui AA, Clark AB. 64.  et al. 2012. Mismatch repair balances leading and lagging strand DNA replication fidelity. PLOS Genet 8:e1003016 [Google Scholar]
  65. Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY. 65.  et al. 2014. Exonuclease mutations in DNA polymerase ε reveal replication strand specific mutation patterns and human origins of replication. Genome Res 24:1740–50 [Google Scholar]
  66. Burgers PM, Gordenin D, Kunkel TA. 66.  2016. Who is leading the replication fork, Pol ε or Pol δ?. Mol. Cell 61:492–93 [Google Scholar]
  67. Johnson RE, Klassen R, Prakash L, Prakash S. 67.  2016. Response to Burgers et al. Mol. Cell 61:494–95 [Google Scholar]
  68. Kelman Z, Lee JK, Hurwitz J. 68.  1999. The single minichromosome maintenance protein of Methanobacteriumthermoautotrophicum ΔH contains DNA helicase activity. PNAS 96:14783–88 [Google Scholar]
  69. Shechter DF, Ying CY, Gautier J. 69.  2000. The intrinsic DNA helicase activity of Methanobacteriumthermoautotrophicum ΔH minichromosome maintenance protein. J. Biol. Chem. 275:15049–59 [Google Scholar]
  70. Fu YV, Yardimci H, Long DT, Ho TV, Guainazzi A. 70.  et al. 2011. Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146:931–41 [Google Scholar]
  71. Li N, Zhai Y, Zhang Y, Li W, Yang M. 71.  et al. 2015. Structure of the eukaryotic MCM complex at 3.8 Å. Nature 524:186–91 [Google Scholar]
  72. Simon AC, Sannino V, Costanzo V, Pellegrini L. 72.  2016. Structure of human Cdc45 and implications for CMG helicase function. Nat. Commun. 7:11638 [Google Scholar]
  73. Yuan Z, Bai L, Sun J, Georgescu R, Liu J. 73.  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]
  74. Abid Ali F, Renault L, Gannon J, Gahlon HL, Kotecha A. 74.  et al. 2016. Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate. Nat. Commun. 7:10708 [Google Scholar]
  75. Samel SA, Fernandez-Cid A, Sun J, Riera A, Tognetti S. 75.  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]
  76. Bruck I, Kaplan DL. 76.  2015. The Dbf4-Cdc7 kinase promotes Mcm2-7 ring opening to allow for single-stranded DNA extrusion and helicase assembly. J. Biol. Chem. 290:1210–21 [Google Scholar]
  77. Johansson E, Dixon N. 77.  2013. Replicative DNA polymerases. Cold Spring Harb. Perspect. Biol. 5:1–14 [Google Scholar]
  78. Makarova KS, Krupovic M, Koonin EV. 78.  2014. Evolution of replicative DNA polymerases in archaea and their contributions to the eukaryotic replication machinery. Front. Microbiol. 5:354 [Google Scholar]
  79. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T. 79.  et al. 2016. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat. Rev. Cancer 16:71–81 [Google Scholar]
  80. Navas TA, Zhou Z, Elledge SJ. 80.  1995. DNA polymerase ε links the DNA replication machinery to the S phase checkpoint. Cell 80:29–39 [Google Scholar]
  81. Lou H, Komata M, Katou Y, Guan Z, Reis CC. 81.  et al. 2008. Mrc1 and DNA polymerase ε function together in linking DNA replication and the S phase checkpoint. Mol. Cell 32:106–17 [Google Scholar]
  82. Hogg M, Johansson E. 82.  2012. DNA polymerase ε.. Subcell. Biochem. 62:237–57 [Google Scholar]
  83. Hogg M, Osterman P, Bylund GO, Ganai RA, Lundström EB. 83.  et al. 2014. Structural basis for processive DNA synthesis by yeast DNA polymerase ε.. Nat. Struct. Mol. Biol. 21:49–55 [Google Scholar]
  84. Chilkova O, Stenlund P, Isoz I, Stith CM, Grabowski P. 84.  et al. 2007. The eukaryotic leading and lagging strand DNA polymerases are loaded onto primer-ends via separate mechanisms but have comparable processivity in the presence of PCNA. Nucleic Acids Res 35:6588–97 [Google Scholar]
  85. Garg P, Stith CM, Sabouri N, Johansson E, Burgers PM. 85.  2004. Idling by DNA polymerase δ maintains a ligatable nick during lagging-strand DNA replication. Genes Dev 18:2764–73 [Google Scholar]
  86. Ganai RA, Zhang XP, Heyer WD, Johansson E. 86.  2016. Strand displacement synthesis by yeast DNA polymerase ε.. Nucleic Acids Res 44:8229–40 [Google Scholar]
  87. Flood CL, Rodriguez GP, Bao G, Shockley AH, Kow YW, Crouse GF. 87.  2015. Replicative DNA polymerase δ but not ε proofreads errors in cis and in trans.. PLOS Genet. 11:e1005049 [Google Scholar]
  88. Sun J, Shi Y, Georgescu RE, Yuan Z, Chait BT. 88.  et al. 2015. The architecture of a eukaryotic replisome. Nat. Struct. Mol. Biol. 22:976–82 [Google Scholar]
  89. Langston LD, Zhang D, Yurieva O, Georgescu RE, Finkelstein J. 89.  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]
  90. Georgescu RE, Langston L, Yao NY, Yurieva O, Zhang D. 90.  et al. 2014. Mechanism of asymmetric polymerase assembly at the eukaryotic replication fork. Nat. Struct. Mol. Biol. 21:664–70 [Google Scholar]
  91. Raschle M, Knipscheer P, Enoiu M, Angelov T, Sun J. 91.  et al. 2008. Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134:969–80 [Google Scholar]
  92. Pellegrini L. 92.  2012. The Pol α-primase complex. Subcell. Biochem. 62:157–69 [Google Scholar]
  93. Klinge S, Nunez-Ramirez R, Llorca O, Pellegrini L. 93.  2009. 3D architecture of DNA Pol α reveals the functional core of multi-subunit replicative polymerases. EMBO J 28:1978–87 [Google Scholar]
  94. Suwa Y, Gu J, Baranovskiy AG, Babayeva ND, Pavlov YI, Tahirov TH. 94.  2015. Crystal structure of the human Pol α B subunit in complex with the C-terminal domain of the catalytic subunit. J. Biol. Chem. 290:14328–37 [Google Scholar]
  95. Netz DJ, Stith CM, Stumpfig M, Kopf G, Vogel D. 95.  et al. 2011. Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes. Nat. Chem. Biol. 8:125–32 [Google Scholar]
  96. Makarova AV, Stodola JL, Burgers PM. 96.  2012. A four-subunit DNA polymerase ζ complex containing Pol δ accessory subunits is essential for PCNA-mediated mutagenesis. Nucleic Acids Res 40:11618–26 [Google Scholar]
  97. Klinge S, Hirst J, Maman JD, Krude T, Pellegrini L. 97.  2007. An iron-sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. Nat. Struct. Mol. Biol. 14:875–77 [Google Scholar]
  98. Weiner BE, Huang H, Dattilo BM, Nilges MJ, Fanning E, Chazin WJ. 98.  2007. An iron-sulfur cluster in the C-terminal domain of the p58 subunit of human DNA primase. J. Biol. Chem. 282:33444–51 [Google Scholar]
  99. Jain R, Vanamee ES, Dzikovski BG, Buku A, Johnson RE. 99.  et al. 2014. An iron-sulfur cluster in the polymerase domain of yeast DNA polymerase ε.. J. Mol. Biol. 426:301–8 [Google Scholar]
  100. Arnold AR, Grodick MA, Barton JK. 100.  2016. DNA charge transport: from chemical principles to the cell. Cell Chem. Biol. 23:183–97 [Google Scholar]
  101. Kilkenny ML, De Piccoli G, Perera RL, Labib K, Pellegrini L. 101.  2012. A conserved motif in the C-terminal tail of DNA polymerase α tethers primase to the eukaryotic replisome. J. Biol. Chem. 287:23740–47 [Google Scholar]
  102. Kilkenny ML, Longo MA, Perera RL, Pellegrini L. 102.  2013. Structures of human primase reveal design of nucleotide elongation site and mode of Pol α tethering. PNAS 110:15961–66 [Google Scholar]
  103. Baranovskiy AG, Babayeva ND, Zhang Y, Gu J, Suwa Y. 103.  et al. 2016. Mechanism of concerted RNA-DNA primer synthesis by the human primosome. J. Biol. Chem. 291:10006–20 [Google Scholar]
  104. Nunez-Ramirez R, Klinge S, Sauguet L, Melero R, Recuero-Checa MA. 104.  et al. 2011. Flexible tethering of primase and DNA Pol α in the eukaryotic primosome. Nucleic Acids Res 39:8187–99 [Google Scholar]
  105. Nethanel T, Reisfeld S, Dinter-Gottlieb G, Kaufmann G. 105.  1988. An Okazaki piece of simian virus 40 may be synthesized by ligation of shorter precursor chains. J. Virol. 62:2867–73 [Google Scholar]
  106. Bullock PA, Seo YS, Hurwitz J. 106.  1991. Initiation of simian virus 40 DNA synthesis in vitro. Mol. Cell. Biol. 11:2350–61 [Google Scholar]
  107. Waga S, Stillman B. 107.  1994. Anatomy of a DNA replication fork revealed by reconstitution of SV40 DNA replication in vitro. Nature 369:207–12 [Google Scholar]
  108. Zlotkin T, Kaufmann G, Jiang Y, Lee MY, Uitto L. 108.  et al. 1996. DNA polymerase ε may be dispensable for SV40—but not cellular—DNA replication. EMBO J 15:2298–305 [Google Scholar]
  109. Tsurimoto T, Stillman B. 109.  1991. Replication factors required for SV40 DNA replication in vitro. II. Switching of DNA polymerase α and δ during initiation of leading and lagging strand synthesis. J. Biol. Chem. 266:1961–68 [Google Scholar]
  110. Yuzhakov A, Kelman Z, Hurwitz J, O'Donnell M. 110.  1999. Multiple competition reactions for RPA order the assembly of the DNA polymerase δ holoenzyme. EMBO J 18:6189–99 [Google Scholar]
  111. Perera RL, Torella R, Klinge S, Kilkenny ML, Maman JD, Pellegrini L. 111.  2013. Mechanism for priming DNA synthesis by yeast DNA polymerase α.. eLife 2:e00482 [Google Scholar]
  112. Mikhailov VS, Bogenhagen DF. 112.  1996. Termination within oligo(dT) tracts in template DNA by DNA polymerase γ occurs with formation of a DNA triplex structure and is relieved by mitochondrial single-stranded DNA-binding protein. J. Biol. Chem. 271:30774–80 [Google Scholar]
  113. Zhang Y, Baranovskiy AG, Tahirov ET, Tahirov TH, Pavlov YI. 113.  2016. Divalent ions attenuate DNA synthesis by human DNA polymerase α by changing the structure of the template/primer or by perturbing the polymerase reaction. DNA Repair 43:24–33 [Google Scholar]
  114. Stodola JL, Burgers PM. 114.  2016. Resolving individual steps of Okazaki-fragment maturation at a millisecond timescale. Nat. Struct. Mol. Biol. 23:402–8 [Google Scholar]
  115. Ganai RA, Osterman P, Johansson E. 115.  2015. Yeast DNA polymerase catalytic core and holoenzyme have comparable catalytic rates. J. Biol. Chem. 290:3825–35 [Google Scholar]
  116. Dieckman LM, Johnson RE, Prakash S, Washington MT. 116.  2010. Pre-steady state kinetic studies of the fidelity of nucleotide incorporation by yeast DNA polymerase δ.. Biochemistry 49:7344–50 [Google Scholar]
  117. Raghuraman MK, Winzeler EA, Collingwood D, Hunt S, Wodicka L. 117.  et al. 2001. Replication dynamics of the yeast genome. Science 294:115–21 [Google Scholar]
  118. Burgers PM. 118.  2009. Polymerase dynamics at the eukaryotic DNA replication fork. J. Biol. Chem. 284:4041–45 [Google Scholar]
  119. Balakrishnan L, Bambara RA. 119.  2013. Flap endonuclease 1. Annu. Rev. Biochem. 82:119–38 [Google Scholar]
  120. Tsutakawa SE, Lafrance-Vanasse J, Tainer JA. 120.  2014. The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once. DNA Repair 19:95–107 [Google Scholar]
  121. Kang YH, Lee CH, Seo YS. 121.  2010. Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 45:71–96 [Google Scholar]
  122. Wanrooij PH, Burgers PM. 122.  2015. Yet another job for Dna2: checkpoint activation. DNA Repair 32:17–23 [Google Scholar]
  123. Levikova M, Cejka P. 123.  2015. The Saccharomycescerevisiae Dna2 can function as a sole nuclease in the processing of Okazaki fragments in DNA replication. Nucleic Acids Res 43:7888–97 [Google Scholar]
  124. Jin YH, Ayyagari R, Resnick MA, Gordenin DA, Burgers PM. 124.  2003. Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and 3′-5′-exonuclease activities of Pol δ in the creation of a ligatable nick. J. Biol. Chem. 278:1626–33 [Google Scholar]
  125. Balakrishnan L, Bambara RA. 125.  2010. Eukaryotic lagging strand DNA replication employs a multi-pathway mechanism that protects genome integrity. J. Biol. Chem. 286:6865–70 [Google Scholar]
  126. Indiani C, McInerney P, Georgescu R, Goodman MF, O'Donnell M. 126.  2005. A sliding-clamp toolbelt binds high- and low-fidelity DNA polymerases simultaneously. Mol. Cell 19:805–15 [Google Scholar]
  127. Beattie TR, Bell SD. 127.  2012. Coordination of multiple enzyme activities by a single PCNA in archaeal Okazaki fragment maturation. EMBO J 31:1556–67 [Google Scholar]
  128. Dovrat D, Stodola JL, Burgers PM, Aharoni A. 128.  2014. Sequential switching of binding partners on PCNA during in vitro Okazaki fragment maturation. PNAS 111:14118–23 [Google Scholar]
  129. Gary R, Park MS, Nolan JP, Cornelius HL, Kozyreva OG. 129.  et al. 1999. A novel role in DNA metabolism for the binding of Fen1/Rad27 to PCNA and implications for genetic risk. Mol. Cell. Biol. 19:5373–82 [Google Scholar]
  130. Vijayakumar S, Chapados BR, Schmidt KH, Kolodner RD, Tainer JA, Tomkinson AE. 130.  2007. The C-terminal domain of yeast PCNA is required for physical and functional interactions with Cdc9 DNA ligase. Nucleic Acids Res 35:1624–37 [Google Scholar]
  131. Ayyagari R, Gomes XV, Gordenin DA, Burgers PM. 131.  2003. Okazaki fragment maturation in yeast. I. Distribution of functions between FEN1 and DNA2. J. Biol. Chem. 278:1618–25 [Google Scholar]
  132. Kadyrov FA, Genschel J, Fang Y, Penland E, Edelmann W, Modrich P. 132.  2009. A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair. PNAS 106:8495–500 [Google Scholar]
  133. Lujan SA, Clausen AR, Clark AB, MacAlpine HK, MacAlpine DM. 133.  et al. 2014. Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition. Genome Res 24:1751–64 [Google Scholar]
  134. Smith DJ, Whitehouse I. 134.  2012. Intrinsic coupling of lagging-strand synthesis to chromatin assembly. Nature 483:434–38 [Google Scholar]
  135. Sinha NK, Morris CF, Alberts BM. 135.  1980. Efficient in vitro replication of double-stranded DNA templates by a purified T4 bacteriophage replication system. J. Biol. Chem. 255:4290–93 [Google Scholar]
  136. Chastain PD II, Makhov AM, Nossal NG, Griffith J. 136.  2003. Architecture of the replication complex and DNA loops at the fork generated by the bacteriophage T4 proteins. J. Biol. Chem. 278:21276–85 [Google Scholar]
  137. Hamdan SM, Loparo JJ, Takahashi M, Richardson CC, van Oijen AM. 137.  2009. Dynamics of DNA replication loops reveal temporal control of lagging-strand synthesis. Nature 457:336–39 [Google Scholar]
  138. Ishmael FT, Trakselis MA, Benkovic SJ. 138.  2003. Protein-protein interactions in the bacteriophage T4 replisome. The leading strand holoenzyme is physically linked to the lagging strand holoenzyme and the primosome. J. Biol. Chem. 278:3145–52 [Google Scholar]
  139. McHenry CS. 139.  2011. DNA replicases from a bacterial perspective. Annu. Rev. Biochem. 80:403–36 [Google Scholar]
  140. Simon AC, Zhou JC, Perera RL, van Deursen F, Evrin C. 140.  et al. 2014. A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome. Nature 510:293–97 [Google Scholar]
  141. Villa F, Simon AC, Ortiz Bazan MA, Kilkenny ML, Wirthensohn D. 141.  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]
  142. Bermudez VP, Farina A, Tappin I, Hurwitz J. 142.  2010. Influence of the human cohesion establishment factor Ctf4/AND-1 on DNA replication. J. Biol. Chem. 285:9493–505 [Google Scholar]
  143. Samora CP, Saksouk J, Goswami P, Wade BO, Singleton MR. 143.  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]
  144. Hanna JS, Kroll ES, Lundblad V, Spencer FA. 144.  2001. Saccharomycescerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. Mol. Cell. Biol. 21:3144–58 [Google Scholar]
  145. Fumasoni M, Zwicky K, Vanoli F, Lopes M, Branzei D. 145.  2015. Error-free DNA damage tolerance and sister chromatid proximity during DNA replication rely on the Polα/Primase/Ctf4 complex. Mol. Cell 57:812–23 [Google Scholar]
  146. Williams DR, McIntosh JR. 146.  2002. mcl1+, the Schizosaccharomycespombe homologue of CTF4, is important for chromosome replication, cohesion, and segregation. Eukaryot. Cell 1:758–73 [Google Scholar]
  147. Calzada A, Hodgson B, Kanemaki M, Bueno A, Labib K. 147.  2005. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev 19:1905–19 [Google Scholar]
/content/journals/10.1146/annurev-biochem-061516-044709
Loading
/content/journals/10.1146/annurev-biochem-061516-044709
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error