Herpes Simplex Virus Type 1 DNA Polymerase: Eukaryotic Model Enzyme and Principal Target of Antiviral Therapy

  • Charles W. Knopf
  • Reiner Strick
Part of the Frontiers of Virology book series (FRVIROLOGY, volume 3)


As the major essential function of the viral DNA replication machinery, the herpes simplex virus (HSV) DNA polymerase (Pol) represents the ultimate target of many currently used antiherpetic drugs. Since development of antiviral drug resistance may occur for all of these drugs and has already become an important clinical issue, there is an apparent need for other targets which allow drugs to be designed which are to a lesser extent affected by drug resistance. Potential new targets are the recently identified novel interactions of HSV Pol and the viral replication proteins, which have been shown to be essential for viral DNA replication. This review tries to provide an insight into our present knowledge of the structural and functional analysis of HSV Pol, which has become an attractive model enzyme for studies of eukaryotic Pol. The extensive computer analysis carried out by several laboratories on the primary protein sequence of prokaryotic and eukaryotic Pol reveals that DNA-dependent and RNA-dependent Pol are similarly organized. Major replicative enzymes possess both a proofreading exonuclease and a polymerization activity, and according to the sequence comparison these catalytic functions are organized in analogous and separate protein entities, designated exonuclease and polymerization domain, as observed with the prokaryotic Escherichia coli Pol I. An updated sequence alignment indicates that amongst the cellular polymerase species, the HSV Pol is more related to the eukaryotic Pol δ, suggesting that the viral enzyme derives from an ancestor of the latter polymerase. Like this major DNA replicase, the HSV Pol has a proofreading function and is associated with an additional subunit. Furthermore, the close relationship is documented by the identical behavior to common replication inhibitors.

Genetic studies and the biochemical analysis of the HSV Pol have emphasized that the herpesviral enzyme may specify at least four distinct functions that are required for the faithful replication of herpesvirus DNA in vivo. Three of these functions can be correlated with known properties of the HSV enzyme such as polymerization activity, proofreading exonuclease, and association of a viral replication protein. The fourth function, which could correspond to a recently identified RNase H activity, is controversial.

Recent progress has been made in the analysis of the DNA template interaction of HSV Pol. Using a DNA-binding assay, it will be shown that many compounds known to inhibit the Pol activity exert a pronounced effect on the DNA-binding property of the enzyme. By employing a set of monospecific antibodies, directed against partially overlapping peptide domains of HSV-1 Pol of strain Angelotti, two antibodies which neutralized both catalytic activities of the enzyme were shown to interfere with DNA binding. The currently available information from structural modeling of E. coil Pol I and human immunodeficiency type 1 (HIV- l) reverse transcriptase, biochemical analysis, and antibody supershift experiments were combined into a working model for the HSV Pol holoenzyme. The usefulness of the identified protein-protein and protein-DNA interactions of HSV Pol and an auxiliary virus protein as possible novel targets for antiherpetic therapy are discussed.


Herpes Simplex Virus Type Antiviral Therapy Exonuclease Activity Klenow Fragment Principal Target 
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  1. Abbotts J, Nishiyama Y, Yoshida S, Loeb LA (1987) On the fidelity of DNA replication: herpes DNA polymerase and its associated exonuclease. Nucleic Acids Res 15: 1185–1198PubMedCrossRefGoogle Scholar
  2. Albrecht JC, Fleckenstein B (1990) Structural organization of the conserved gene block of herpesvirus saimiri coding for DNA polymerase, glycoprotein B, and major DNA binding protein. Virology 174: 533–542PubMedCrossRefGoogle Scholar
  3. Andrei G, Snoeck R, Goubau P, Desmyter J, De Clercq E (1992) Comparative activity of various compounds against clinical strains of herpes simplex virus. Eur J Clin Microbiol Infect Dis 11: 143–151PubMedCrossRefGoogle Scholar
  4. Aron GM, Purifoy DJM, Schaffer PA (1975) DNA synthesis and DNA polymerase activity of herpes simplex virus type 1 temperature-sensitive mutants. J Virol 16: 498–507PubMedGoogle Scholar
  5. Baer R, Bankier AT, Beggin MD, Deininger PL, Farrell PL, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Seguin C, Tuffnell PS, Barrel] BG (1984) DNA sequence and expression of the B95–8 Epstein-Barr virus genome. Nature 310: 207–211PubMedCrossRefGoogle Scholar
  6. Baltimore D (1974) Is terminal deoxynucleotidyl transferase a somatic mutagen in lymphocytes? Nature 248: 409–411PubMedCrossRefGoogle Scholar
  7. Banks L, Purifoy DJM, Hurst P-F, Killington RA, Powell KL (1983) Herpes simplex virus non-structural proteins. IV. Purification of the virus-induced deoxyribonuclease and characterization of the enzyme using monoclonal antibodies. J Gen Virol 64: 2249–2260PubMedCrossRefGoogle Scholar
  8. Banks LM, Halliburton IW, Purifoy DJM, Killington RA, Powell KL (1985) Studies on the herpes simplex virus alkaline nuclease: detection of type-common and type-specific epitopes on the enzyme. J Gen Virol 66: 1–14PubMedCrossRefGoogle Scholar
  9. Bapat AR, Han F-S, Liu Z, Zhou B-S, Cheng Y-C (1987) Studies on DNA topoisomerases I and II in herpes simplex virus type 2-infected cells. J Gen Virol 68: 2231–2237PubMedCrossRefGoogle Scholar
  10. Barnes MH, Hammond RA, Kennedy CC, Mack SL, Brown NC (1992) Localization of the exonuclease and polymerase domains of Bacillus subtilis DNA polymerase III. Gene 111: 43–49PubMedCrossRefGoogle Scholar
  11. Beese LS, Steitz TA (1991) Structural basis for the 3’-5’ exonuclease activity of Escherichia coli DNA polymerase I: a two metal ion mechanism. EMBO J 10: 25–33PubMedGoogle Scholar
  12. Bennet LL, Shannon WM, Allen PW, Amen G (1978) Studies on the biochemical basis for the antiviral activities of some nucleoside analogs. Ann N Y Acad Sci 255: 342–352CrossRefGoogle Scholar
  13. Bernad A, Zaballos A, Salas M, Blanco L (1987) Structural and functional relationships between prokaryotic and eukaryotic DNA polymerases. EMBO J 6: 4219–4225PubMedGoogle Scholar
  14. Bernad A, Blanco L, Lâzaro JM, Martin G, Salas M (1989) A conserved 3’ to 5’ exonuclease active site in prokaryotic and eukaryotic DNA polymerases. Cell 59: 219–228PubMedCrossRefGoogle Scholar
  15. Biswal N, Feldan P, Levy CC (1983) A DNA topoisomerase activity copurifies with the DNA polymerase induced by herpes simplex virus. Biochim Biophys Acta 740: 379–389PubMedGoogle Scholar
  16. Blanco L, Bernad A, Blasco MA, Salas M (1990) A general structure for DNA-dependent DNA polymerases. Gene 100: 27–38CrossRefGoogle Scholar
  17. Blanco L, Bernad A, Salas M (1992) Evidence favouring the hypothesis of a conserved 3’-5’ exonuclease active site in DNA-dependent DNA polymerases. Gene 112: 139–144PubMedCrossRefGoogle Scholar
  18. Bludau H, Freese UK (1991) Analysis of the HSV-1 strain 17 DNA polymerase gene reveals the expression of four different classes of pol transcripts. Virology 183: 505–518PubMedCrossRefGoogle Scholar
  19. Boehmer PE, Lehman IR (1993) Herpes simplex virus type 1 ICP8: helix-destabilizing properties. J Virol 67: 711–715PubMedGoogle Scholar
  20. Boehmer PE, Dodson MS, Lehman IR (1993) The herpes simplex virus type-1 origin binding protein. DNA helicase activity. J Biol Chem 268: 1220–1225PubMedGoogle Scholar
  21. Boulet A, Simon M, Faye G, Bauer GA, Burgers PMJ (1989) Structure and function of the Saccharomyces cerevisiae CDC2 gene encoding the large subunit of DNA polymerase III. EMBO J 8: 1849–1854PubMedGoogle Scholar
  22. Branden C, Tooze J (1991) Introduction to protein structure. Garland, New YorkGoogle Scholar
  23. Brown WC, Duncan JA, Campbell JL (1993) Purification and characterization of the Saccharomyces cerevisiae DNA polymerase 8 overproduced in Escherichia coll. J Biol Chem 268: 982–990PubMedGoogle Scholar
  24. Burgers PMJ, Bambara RA, Campbell JL, Chang LMS, Downey KM, Hübscher U, Lee MYWT, Linn SM, So AG, Spadari S (1990) Revised nomenclature for eukaryotic DNA polymerases. Eur J Biochem 191: 617–618PubMedCrossRefGoogle Scholar
  25. Calder JM, Stow ND (1990) Herpes simplex virus helicase-primase: the UL8 protein is not required for DNA-dependent ATPase and DNA helicase activities. Nucleic Acids Res 18: 3573–3578PubMedCrossRefGoogle Scholar
  26. Challberg MD (1986) A method for identifying the viral genes required for herpes DNA replication. Proc Natl Acad Sci USA 83: 9094–9098PubMedCrossRefGoogle Scholar
  27. Challberg MD, Kelly TJ (1989) Animal virus DNA replication. Annu Rev Biochem 58: 671–718PubMedCrossRefGoogle Scholar
  28. Chan BSS, Court DA, Verula PJ, Bertrand H (1991) The kalilo linear senescence-inducing plasmid of neurospora is an invertron and encodes DNA and RNA polymerases. Curr Genet 20: 225–237PubMedCrossRefGoogle Scholar
  29. Chang LMS (1975) The distributive nature of enzymatic DNA synthesis. J Mol Biol 93: 219–235PubMedCrossRefGoogle Scholar
  30. Chang LMS, Bollum FJ (1971) Deoxynucleotide-polymerizing enzymes of calf thymus gland. J Biol Chem 246: 909–916PubMedGoogle Scholar
  31. Chartrand P, Stow ND, Timbury MC, Wilkie NM (1979) Physical mapping of PAAr mutations of herpes simplex virus type 1 and type 2 by intertypic marker rescue. J Virol 31: 265–276PubMedGoogle Scholar
  32. Chiou HC, Weller SK, Coen DM (1985) Mutations in the herpes simplex virus major DNA-binding protein gene leading to altered sensitivity to DNA polymerase inhibitors. Virology 145: 213–226PubMedCrossRefGoogle Scholar
  33. Chung DW, Zhang J, Tan C-K, Davie EW, So AG, Downey KM (1991) Primary structure of the catalytic subunit of human DNA polymerase S and chromosomal location of the gene. Proc Natl Acad Sci USA 88: 11197–11201PubMedCrossRefGoogle Scholar
  34. Coen DM (1986) General aspects of virus drug resistance with special reference to herpes simplex virus. J Antimicrob Agents Chemother 18 [Suppl B]: 1–10CrossRefGoogle Scholar
  35. Coen DM (1991) The implications of resistance to antiviral agents for herpesvirus drug targets and drug therapy. Antiviral Res 15: 287–300PubMedCrossRefGoogle Scholar
  36. Coen DM, Schaffer PA (1980) Two distinct loci can confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci USA 77: 2265–2269PubMedCrossRefGoogle Scholar
  37. Coen DM, Furman PA, Gelep PT, Schaffer PA (1982) Mutations in the herpes simplex virus DNA polymerase gene can confer resistance to 943-arabinosyl adenine. J Virol 41: 909–918PubMedGoogle Scholar
  38. Coen DM, Aschman DP, Gelep PT, Retondo MJ, Weller SK, Schaffer PA (1984) Fine mapping and molecular cloning of mutations in the herpes simplex virus DNA polymerase locus. J Virol 49: 236–247PubMedGoogle Scholar
  39. Cotteril SM, Reyland ME, Loeb LA, Lehman IR (1987) A cryptic proofreading 3’ to 5’ exonuclease associated with the polymerase subunit of the DNA polymerase-primase from Drosophila melanogaster. Proc Natl Acad Sci USA 84: 5635–5639CrossRefGoogle Scholar
  40. Crumpacker CS (1992) Mechanism of action of foscarnet against viral polymerases. Am J Med 92 [suppl 2A]: 3S - 7SPubMedCrossRefGoogle Scholar
  41. Crute JJ, Lehman IR (1989) Herpes simplex- 1DNA polymerase. Identification of an intrinsic 5’-3’ exonuclease with ribonuclease H activity. J Biol Chem 264: 19266–19270PubMedGoogle Scholar
  42. Crute JJ, Mocarski ES, Lehman IR (1988) A DNA helicase induced by herpes simplex virus type 1. Nucleic Acids Res 16: 6585–6596PubMedCrossRefGoogle Scholar
  43. Crute JJ, Tsurumi T, Zhu L, Weller SK, Olivo PD, Challberg MD, Mocarski ES, Lehman IR (1989) Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products. Proc Natl Acad Sci USA 86: 2186–2189PubMedCrossRefGoogle Scholar
  44. Dabrowski CE, Schaffer PA (1991) Herpes simplex virus type 1 origin-specific binding protein: oriS-binding properties and effects of cellular proteins. J Virol 65: 3140–3150PubMedGoogle Scholar
  45. Dahlberg ME, Benkovic SJ (1991) Kinetic mechanism of DNA polymerase I (Klenow fragment): identification of a second conformational change and evaluation of the internal equilibrium constant. Biochemistry 30: 4835–4843PubMedCrossRefGoogle Scholar
  46. Davison AJ (199) Channel catfish virus: a new type of herpesvirus. EMBL Data Library, HeidelbergGoogle Scholar
  47. Davison AJ, Scott JE (1986). The complete DNA sequence of Varicella-zoster virus. J Gen Virol 67: 1759–1816PubMedCrossRefGoogle Scholar
  48. De Bruyn Kops A, Knipe DM (1988) Formation of DNA replication structures in herpes virus-infected cells requires a viral DNA binding protein. Cell 55: 857–868PubMedCrossRefGoogle Scholar
  49. De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Holy A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8: 261–272PubMedCrossRefGoogle Scholar
  50. Delarue M, Poch O, Tordo N, Moras D, Argos P (1990) An attempt to unify the structure of polymerases. Protein Eng 3: 461–467PubMedCrossRefGoogle Scholar
  51. Derbyshire V, Freemont PS, Sanderson MR, Beese LS, Friedman JM, Joyce CM, Steitz TA (1988) Genetic and crystallographic studies of the 3’,5’-exonucleolytic site of DNA polymerase I. Science 240: 199–201PubMedCrossRefGoogle Scholar
  52. Derbyshire V, Grindley NDF, Joyce CM (1991) The 3’-5’ exonuclease of DNA polymerase I of Escherichia call: contribution of each amino acid at the active site to the reaction. EMBO J 10: 17–24PubMedGoogle Scholar
  53. Deutscher MP, Kornberg A (1969) Enzymatic synthesis of deoxyribonucleic acid. XXVIII. The pyrophosphate exchange and pyrophosphorolysis reactions of deoxyribonucleic acid polymerase. J Biol Chem 244: 3019–3028PubMedGoogle Scholar
  54. Devereux J, Haeberli P, Smithies O (1984) A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res 12: 387–395PubMedCrossRefGoogle Scholar
  55. Digard P, Coen DM (1990) A novel functional domain of an ot-like DNA polymerase. The binding site on the herpes simplex virus polymerase for the viral UL42 protein. J Biol Chem 265: 17393–17396PubMedGoogle Scholar
  56. Digard P, Bebrin WR, Weisshart K, Coen DM (1993a) The extreme C terminus of herpes simplex virus DNA polymerase is crucial for functional interaction with processivity factor UL42 and for viral replication. J Virol 67: 398–406PubMedGoogle Scholar
  57. Digard P, Chow CS, Pirrit L, Coen DM (1993b) Functional analysis of the herpes simplex virus UL42 protein. J Virol 67: 1159–1168PubMedGoogle Scholar
  58. Dodson MS, Lehman IR (1991) Association of DNA helicase and primase activities with a subassembly of the herpes simplex virus 1 helicase-primase composed of the UL5 and UL52 gene products. Proc Natl Acad Sci USA 88: 1105–1109PubMedCrossRefGoogle Scholar
  59. Dodson MS, Lehman IR (1993) The herpes simplex virus type I origin binding protein. DNA-dependent nucleoside triphosphatase activity. J Biol Chem 268: 1213–1219PubMedGoogle Scholar
  60. Dodson MS, Crute JJ, Bruckner RC, Lehman IR (1989) Overexpression and assembly of the herpes simplex virus type I helicase-primase in insect cells. J Biol Chem 26: 20835–20838Google Scholar
  61. Doolittle RF (1981) Similar amino acid sequences: chance or common ancestry? Science 214: 149–159PubMedCrossRefGoogle Scholar
  62. Dorsky DI, Crumpacker CS (1988) Expression of herpes simplex virus type 1 DNA polymerase gene by in vitro translation and effects of gene deletions on activity. J Virol 62: 32243232Google Scholar
  63. Dorsky DI, Crumpacker CS (1990) Site-specific mutagenesis of a highly conserved region of the herpes simplex virus type 1 DNA polymerase gene. J Virol 64: 1394–1397PubMedGoogle Scholar
  64. Dorsky DI, Chatis P, Crumpacker CS (1987) Functional expression of a cloned herpes simplex virus type 1 DNA polymerase gene. J Virol 61: 1704–1707PubMedGoogle Scholar
  65. Downey KM, Tan C-K, Andrews DM, Li X, So AG (1988) Proposed roles for DNA polymerases alpha and delta at the replication fork. Cancer Cells 6: 403–410Google Scholar
  66. Downey KM, Tan C-K, So AG (1990) DNA polymerase delta: a second eukaryotic DNA replicase. BioEssays 12: 231–236PubMedCrossRefGoogle Scholar
  67. Elion G, Furman PA, Fyfe JA, De Miranda P, Beauchamp L, Schaeffer HJ (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc Natl Acad Sci USA 74: 5716–5720PubMedCrossRefGoogle Scholar
  68. Elliot R, Clark C, Jaquish D, Spector DH (1991) Transcription analysis and sequence of the putative murine cytomegalovirus DNA polymerase gene. Virology 185: 169–186CrossRefGoogle Scholar
  69. Englund PT, Huberman JA, Jovin TM, Kornberg A (1969) Enzymatic synthesis of deoxyribonucleic acid. XXX. Binding of triphosphates to deoxyribonucleic acid polymerase. J Biol Chem 244: 3038–3044PubMedGoogle Scholar
  70. Fierer DS, Challberg MD (1992) Purification and characterization of UL9, the herpes simplex virus type l origin-binding protein. J Virol 66: 3986–3995PubMedGoogle Scholar
  71. Foury F (1989) Cloning and sequencing of the nuclear gene MIP1 encoding the catalytic subunit of the yeast mitochondrial DNA polymerase. J Biol Chem 264: 20552–20560PubMedGoogle Scholar
  72. Frank KB, Cheng Y-C (1985) M utually exclusive inhibition of herpesvirus DNA polymerase by aphidicolin, phosphonoformate, and acyclic nucleoside triphosphates. Antimicrob Agents Chemother 27: 445–448PubMedGoogle Scholar
  73. Frank KB, Derse DD, Bastow KF, Cheng Y-C (1984) Novel interaction of aphidicolin with herpes simplex virus DNA polymerase and polymerase-associated exonuclease. J Biol Chem 259: 13282–13286PubMedGoogle Scholar
  74. Freemont PS, 011is DL, Steitz TA, Joyce CM (1986) A domain of the Klenow fragment of Escherichia coli DNA polymerase I has polymerase but no exonuclease activity. Proteins Struct Funct Genet 1: 66–73PubMedCrossRefGoogle Scholar
  75. Freemont PS, Friedman JM, Beese LS, Sanderson MR, Steitz TA (1988) Co-crystal structure of an editing complex of Klenow fragment with DNA. Proc Natl Acad Sci USA 85: 8924–8928PubMedCrossRefGoogle Scholar
  76. Fridlender B, Chejanovsky N, Becker Y (1978) Selective inhibition of herpes simplex virus type 1 DNA polymerase by zinc ions. Virology 84: 551–554PubMedCrossRefGoogle Scholar
  77. Fry M, Loeb LA (1986) Animal cell DNA polymerises. CRC Press, Boca RatonGoogle Scholar
  78. Furman PA, St. Clair MH, Fyfe JA, Rideout JL, Keller PM, Elion GB (1979) Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl) guanine and its triphosphate. J Virol 32: 72–77PubMedGoogle Scholar
  79. Furman PA, Coen DM, St Clair MH, Schaffer PA (1981) Acyclovir-resistant mutants of herpes simplex virus type I express altered DNA polymerase or reduced acyclovir phosphorylating activities. J Virol 40: 936–941PubMedGoogle Scholar
  80. Fyfe JA, Keller PM, Furman PA, Miller RL, Elion GB (1978) Thymidine kinase herpes simplex virus phosphorylates the new antiviral compound 9-(2-hydroxyethomethyl)guanine. J Biol Chem 253: 8721–8727PubMedGoogle Scholar
  81. Gao M, Knipe DM (1989) Genetic evidence for multiple nuclear function of the herpes simplex virus ICP8 DNA-binding protein. J Virol 63: 5258–5267.PubMedGoogle Scholar
  82. Gao M, Knipe DM (1993) Intragenic complementation of herpes simplex virus ICP8 DNA-binding protein mutants. J Virol 67: 876–885PubMedGoogle Scholar
  83. Gallo ML, Jackwood DH, Murphy M, Marsden HS, Parris DS (1988) Purification of the herpes simplex virus type 1 65 kilodalton protein and evidence for its association with the virus-encoded DNA polymerase. J Virol 62: 2874–2883PubMedGoogle Scholar
  84. Gallo ML, Dorsky DI, Crumpacker CS, Parris DS (1989) The essential 65-kilodalton DNA-binding protein of herpes simplex virus stimulates the virus-encoded DNA polymerase. J Virol 63: 5023–5029PubMedGoogle Scholar
  85. Gibbs JS, Chiou HC, Hall JD, Mount DW, Retondo MJ, Weller SK, Coen DM (1985) Sequence and mapping analyses of the herpes simplex virus DNA polymerase gene predict a C-terminal substrate binding domain. Proc Natl Acad Sci USA 82: 7969–7973PubMedCrossRefGoogle Scholar
  86. Gibbs JS, Chiou H, Bastow KF, Cheng YC, Coen DM (1988) Identification of amino acids in herpes simplex virus DNA polymerase involved in substrate and drug recognition. Proc Natl Acad Sci USA 85: 6672–6676PubMedCrossRefGoogle Scholar
  87. Gibbs JS, Weisshart K, Digard P, De Bruyn-Kops A, Knipe DM, Coen DM (1991) Polymerization activity of an a-like DNA polymerase requires a conserved 3’-5’ exonuclease active site. Mol Cell Biol 11: 4786–4795PubMedGoogle Scholar
  88. Gottlieb J, Marcy AI, Coen DM, Challberg MD (1990) The herpes simplex virus type 1 UL42 gene product: a subunit of DNA polymerase that functions to increase processivity. J Virol 64: 5976–5987PubMedGoogle Scholar
  89. Haffey ML, Stevens JT, Terry BJ, Dorsky DI, Crumpacker CS, Wietstock SM, Ruyechan WT, Field AK (1988) Expression of herpes simplex virus type 1 DNA polymerase in Saccharomyces cerevisiae and detection of virus-specific enzyme activity in cell free lysates. J Virol 62: 4493–4498PubMedGoogle Scholar
  90. Haffey ML, Novotny J, Bruccoleri RE, Carroll RD, Stevens JT, Matthews JT (1990) Structure-function studies of the herpes simplex virus type 1 DNA polymerase. J Virol 64: 5008–5018PubMedGoogle Scholar
  91. Hall JD, Furman PA, St. Clair MH, Knopf CW (1985) Reduced in vivo mutagenesis by mutant herpes simplex DNA polymerase involves improved nucleotide selection. Proc Natl Acad Sci USA 82: 3889–3893PubMedCrossRefGoogle Scholar
  92. Hall JD, Wang Y, Pierpont J, Berlin MS, Rundlett SE, Woodward S (1989) Aphidicolin resistance in herpes simplex virus type I reveals features of the DNA polymerase dNTP binding site. Nucleic Acids Res 17: 9231–9244PubMedCrossRefGoogle Scholar
  93. Hart GJ, Boehme RE (1992) The effect of the UL42 protein on the DNA polymerase activity of the catalytic subunit of the DNA polymerase encoded by herpes simplex virus type 1. FEBS Lett 305: 97–100PubMedCrossRefGoogle Scholar
  94. Hay J, Moss H, Halliburton IW (1971) Induction of deoxyribonucleic acid polymerase and deoxyribonuclease activities in cells infected with herpes simplex virus type II. Biochem J 124: 64 pGoogle Scholar
  95. Hernandez TR, Lehman IR (1990) Functional interaction between the herpes simplex-1 DNA polymerase and UL42 protein. J Biol Chem 265: 1 1227–1 1 232Google Scholar
  96. Hirose F, Yamaguchi M, Nishida Y, Masutani M (1991) Structure and expression during development of Drosophila melanogaster gene for DNA polymerase alpha. Nucleic Acids Res 19: 4991–4998PubMedCrossRefGoogle Scholar
  97. Hoffmann PJ (1991) Mechanism of degradation of duplex DNA by the DNase induced by herpes simplex virus. J Virol 38: 1005–1014Google Scholar
  98. Hoffmann PJ, Cheng Y-C (1979) DNase induced after infection of KB cells by herpes simplex virus type 1 or type 2. II. Characterization of an associated endonuclease activity. J Virol 32: 449–457PubMedGoogle Scholar
  99. Holland LE, Sandri-Goldin RM, Goldin AL, Glorioso JC, Levine ML (1984) Transcriptional and genetic analyses of the herpes simplex virus type 1 genome: coordinates 0.29 to 0.45. J Virol 49: 947–955PubMedGoogle Scholar
  100. Hwang CB, Ruffner KL, Coen DM (1992) A point mutation within a distinct conserved region of the herpes simplex virus DNA polymerase gene confers drug resistance. J Virol 66: 1774–1776PubMedGoogle Scholar
  101. Ito J, Braithwaite DK (1991) Compilation and alignment of DNA polymerase sequences. Nucleic Acids Res 19: 4045–4057PubMedCrossRefGoogle Scholar
  102. Johnson PA, Best MG, Friedman T, Parris DS (1991) Isolation of a herpes simplex virus type 1 mutant deleted for the essential UL42 gene and characterization of its null phenotype. J Virol 65: 700–710PubMedGoogle Scholar
  103. Joyce CM (1991) Can DNA polymerase I (Klenow fragment) serve as a model for other DNA polymerases? Curr Opin Struct Biol 1: 123–129CrossRefGoogle Scholar
  104. Joyce CM, Steitz TA (1987) DNA polymerase I: from crystal structure to function via genetics. Curr Opin Struct Biol 1: 123–129CrossRefGoogle Scholar
  105. Jung G, Leavitt MC, Hsieh J-C, Ito J (1987) Bacteriophage PRD1 DNA polymerase: evolution of DNA polymerases. Proc Natl Acad Sci USA 8: 8287–8291CrossRefGoogle Scholar
  106. Keir HM, Gold E (1963) Deoxyribonucleic acid nucleotidyltransferase and deocyribonuclease from cultured cells infected with herpes simplex virus. Biochim Biophys Acta 72: 263–276CrossRefGoogle Scholar
  107. Keir HM, Subak-Sharpe H, Shedden WIH, Watson DH, Wildy P (1966) Immunological evidence for a specific DNA polymerase produced after infection by herpes simplex virus. Virology 30: 154–157PubMedCrossRefGoogle Scholar
  108. Kesti T, Syväoja (1991) Identification and tryptic cleavage of the catalytic core of Hela and calf thymus DNA polymerase s. J Biol Chem 266: 6336–6341Google Scholar
  109. Knopf KW (1979) Properties of herpes simplex virus DNA polymerase and characterization of its associated exonuclease activity. Eur J Biochem 98: 231–244PubMedCrossRefGoogle Scholar
  110. Knopf C (1983) HSV DNA polymerase: highly purified enzyme preparations contain both, 3’ to 5’ and 5’ to 3’ directed exonucleolytic activities. VIIIth international herpesvirus workshop, Oxford, 31 July-5 Aug, p 289Google Scholar
  111. Knopf CW (1986) Nucleotide sequence of the DNA polymerase gene of herpes simplex virus type 1 strain Angelotti. Nucleic Acids Res 14: 8225–8226PubMedCrossRefGoogle Scholar
  112. Knopf CW (1987) The herpes simplex virus type 1 DNA polymerase gene: site of phosphonoacetic acid resistance mutation in strain Angelotti is highly conserved. J Gen Virol 68: 1429–1433PubMedCrossRefGoogle Scholar
  113. Knopf CW, Weisshart K (1988) The herpes simplex virus DNA polymerase: analysis of the functional domains. Biochim Biophys Acta 951: 298–314PubMedGoogle Scholar
  114. Knopf CW, Weisshart K (1990) Comparison of exonucleolytic activities of herpes simplex virus type I DNA polymerase and DNase. Eur J Biochem 191: 263–273PubMedCrossRefGoogle Scholar
  115. Knopf KW, Kaufman ER, Crumpacker C (1981) Physical mapping of drug resistance mutations defines an active center of the herpes simplex virus DNA polymerase enzyme. J Virol 39: 746–757PubMedGoogle Scholar
  116. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256: 1783–1790PubMedCrossRefGoogle Scholar
  117. Kornberg A (1980) DNA replication. Freeman, San FranciscoGoogle Scholar
  118. Kouzarides T, Bankier AT, Satchwell SC, Weston K, Tomlinson P, Barrell BG (1987) Sequence and transcription analysis of the human cytomegalovirus DNA polymerase gene. J Virol 61: 125–133PubMedGoogle Scholar
  119. Kronenwett R., Weisshart K., Knopf CW (1990) Expression of functional herpes simplex virus type I DNA polymerase using recombinant vaccinia virus. VIIIth international congress of virology, Berlin, 26–31 AugGoogle Scholar
  120. Kunkel TA (1992) DNA replication fidelity. J Biol Chem 267: 18251–18254PubMedGoogle Scholar
  121. Larder BA, Kemp SD, Darby G (1987) Related functional domains in virus DNA polymerases. EMBO J 6: 169–175PubMedGoogle Scholar
  122. Leavitt MC, Ito J (1989) T5 DNA polymerase: structural-functional relationships to other DNA polymerases. Proc Natl Acad Sci USA 86: 4465–4469PubMedCrossRefGoogle Scholar
  123. Lecomte PJ, Ninio J (1988) Nucleotide excision by E. coli DNA polymerase I in proofreading and non-proofreading modes. Biochim Biophys Acta 951: 255–260PubMedGoogle Scholar
  124. Leinbach SS, Heath LS (1988) A carboxyl-terminal peptide of the DNA-binding protein ICP8 of herpes simplex virus contains a single-stranded DNA-binding site. Virology 166: 10–16PubMedCrossRefGoogle Scholar
  125. Leinbach SS, Reno JM, Lee LF, Isbell AF, Boezi JA (1976) Mechanism of phosphonoacetic acid inhibition of herpes virus induced DNA polymerase. Biochemistry 15: 426–430PubMedCrossRefGoogle Scholar
  126. Marchetti ME, Smith CA, Schaffer PA (1988) A temperature-sensitive mutation in a herpes simplex virus type I gene required for viral DNA synthesis maps to coordinates 0.609 through 0.614 in UL. J Virol 62: 715–721PubMedGoogle Scholar
  127. Marcy AI, Yager DR, Coen DM (1990a) Isolation and characterization of herpes simplex virus mutants containing engineered mutations at the polymerase locus. J Virol 64: 2208–2216PubMedGoogle Scholar
  128. Marcy AI, Hwang CBC, Ruffner KL, Coen DM (1990b) Engineered herpes simplex virus DNA polymerase point mutants: the most highly conserved region shared among a-like DNA polymerases is involved in substrate recognition. J Virol 64: 5883–5890PubMedGoogle Scholar
  129. Marcy AI, Olivo PD, Challberg MD, Coen DM (1990c) Enzymatic activities of overexpressed herpes simplex virus DNA polymerase purified from recombinant baculovirus-infected cells. Nucleic Acids Res 18: 1207–1215PubMedCrossRefGoogle Scholar
  130. Matthews JT, Stevens JT, Terry BJ, Cianci CW, Haffey ML (1990) Neutralization of purified herpes simplex virus DNA polymerase by two antipeptide sera. Virus Genes 3: 343–354PubMedCrossRefGoogle Scholar
  131. Matthews JT, Terry BJ, Field AK (1993) The structure and function of the HSV DNA replication proteins: defining novel antiviral targets. Antiviral Res 20: 89–114PubMedCrossRefGoogle Scholar
  132. McGeoch DJ, Dolan A, Donald S, Brauer DHK (1986) Complete DNA sequence of the short repeat region in the genome of herpes simplex virus type 1. Nucleic Acids Res 14: 1727–1745PubMedCrossRefGoogle Scholar
  133. McGeoch DJ, Dalrymple MA, Davison AJ, Dolan A, Frame MC, McNab D, Perry LJ, Scott JE, Taylor P (1988) The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. J Virol 69: 1531–1574CrossRefGoogle Scholar
  134. Mildvan A (1989) NMR studies of the interactions of substrates with enzymes and their peptide fragments. FASEB J 3: 1705–1714PubMedGoogle Scholar
  135. Miller WH, Miller RL (1980) Phosphorylation of acyclovir monophosphate by GMP kinase. J Biol Chem 255: 7204–7207PubMedGoogle Scholar
  136. Miller WH, Miller RL (1982) Phosphorylation of acyclovir diphosphate by cellular enzymes. Biochem Pharmacol 31: 3879–3884PubMedCrossRefGoogle Scholar
  137. Morrison A, Sugino A (1991) Nucleotide sequence of the POL3 gene encoding DNA polymerase III (8) of Saccharomyces cerevisiae. Nucleic Acids Res 20: 375CrossRefGoogle Scholar
  138. Morrison A, Araki H, Clark AB, Hamatake RK, Sugino A (1990) A third essential DNA polymerase in S. cerevisiae. Cell 62: 1143–1151PubMedCrossRefGoogle Scholar
  139. Morrison A, Be11 JB, Kunkel TA, Sugino A (1991) Eukaryotic DNA polymerase amino acid sequence required for 3’-5’ exonuclease activity. Proc Natl Acad Sci USA 88: 9473–9477PubMedCrossRefGoogle Scholar
  140. Müller WEG, Zahn RK, Arendes J, Falke D (1979) Oligoribonucleotide initiators for herpessimplex virus DNA synthesis in vivo and in vitro. Virology 98: 200–210PubMedCrossRefGoogle Scholar
  141. Mullen GP, Serpersu EH, Ferrin LJ, Loeb LA (1990) Metal binding to DNA polymerase I, its large fragment, and two 3’-5’ exonuclease mutants of the large fragment. J Biol Chem 265: 14327–14334PubMedGoogle Scholar
  142. O’Donnell ME, Elias P, Lehman IR (1987) Processive replication of single-stranded DNA templates by the herpes simplex virus-induced DNA polymerase. J Biol Chem 262: 4252–4259PubMedGoogle Scholar
  143. Olivo PD, Nelson NJ, Challberg MD (1988) Herpes simplex virus DNA replication: the UL9 gene encodes an origin-binding protein. Proc Natl Acad Sci USA 85: 5414–5418PubMedCrossRefGoogle Scholar
  144. Olivo PD, Nelson NJ, Challberg MD (1989) Herpes simplex virus type 1 gene products required for DNA replication: identification and overexpression. J Virol 63: 196–204PubMedGoogle Scholar
  145. is DL, Brick P, Hamlin R, Xuong NG, Steitz TA (1985a) Structure of large fragment of Escherichia coli DNA polymerase I complexed with dTMP. Nature 313: 762–766PubMedCrossRefGoogle Scholar
  146. is DL, Kline C, Steitz TA (1985b) Domain of E. coil DNA polymerase I showing sequence homology to T7 DNA polymerase. Nature 313: 818–819PubMedCrossRefGoogle Scholar
  147. Ostrander M, Cheng Y-H (1980) Properties of herpes simplex virus type 1 and type 2 DNA polymerase. Biochim Biophys Acta 609: 232–245PubMedGoogle Scholar
  148. Owsianka AM, Hart G, Murphy M, Gottlieb J, Boehme R, Challberg M, Marsden HS (1993) Inhibition of herpes simplex virus type 1 DNA polymerase activity by peptides from the UL42 accessory protein is largely nonspecific. J Virol 67: 258–264PubMedGoogle Scholar
  149. Paillard M, SederoffRR, Levings III CS (1985) Nucleotide sequence of the S-1 mitochondrial DNA from the S cytoplasm of maize. EMBO J 4: 1125–1128Google Scholar
  150. Pandey VN, Williams KR, Stone KL, Modak MJ (1987) Photoaffinity labeling of the thymidine triphosphate binding domain in Escherichia coli DNA polymerase I: Identification of histidine-881 as the site of cross-linking. Biochemistry 26: 7744–7748PubMedCrossRefGoogle Scholar
  151. Patel SS, Wong I, Johnson KA (1991) Pre-steady-state kinetic analysis of processive DNA replication, including complete characterization of an exonuclease-deficient mutant. Biochemistry 30: 511–525PubMedCrossRefGoogle Scholar
  152. Pedrali-Noy G, Spadari S (1980) Mechanism of inhibition of herpes simplex virus and vaccina virus DNA polymerases by aphidicolin, a highly specific inhibitor of DNA replication in eucaryotes. J Virol 36: 457–464PubMedGoogle Scholar
  153. Pizzagalli A, Valsasnini P, Plevani P, Lucchini G (1988) DNA polymerase I gene of Saccharomyces cerevisiae: nucleotide sequence, mapping of a temperature-sensitive mutation, and protein homology with other DNA polymerases. Proc Natl Acad Sci USA 85: 3772–3776PubMedCrossRefGoogle Scholar
  154. Polesky AH, Steitz TA, Grindley NDF, Joyce CM (1990) Identification of residues critical for the polymerase activity of the Klenow fragment of DNA polymerase I from Escherichia coli. J Biol Chem 265: 14579–14591PubMedGoogle Scholar
  155. Polesky AH, Dahlberg ME, Benkovic SJ, Grindley NDF, Joyce CM (1992) Side chains involved in catalysis of the polymerase reaction of DNA polymerase I from Escherichia coli. J Biol Chem 267: 8417–8428PubMedGoogle Scholar
  156. Powell K, Purifoy (1977) Nonstructural proteins of the herpes simplex virus 1. Purification of the induced DNA polymerase. J Virol 24: 618–626PubMedGoogle Scholar
  157. Purifoy DJM, Lewis RB, Powell KL (1977) Identification of the herpes virus DNA polymerase gene. Nature 269: 621–623PubMedCrossRefGoogle Scholar
  158. Quinn JP, McGeoch DJ (1985) DNA sequence of the region in the genome of herpes simplex virus type 1 containing the genes for DNA polymerase and the major DNA binding protein. Nucleic Acids Res 13: 8143–8163PubMedCrossRefGoogle Scholar
  159. Reddy MK, Weitzel SE, von Hippel, PH (1992) Processive proofreading is intrinsic to T4 DNA polymerase. J Biol Chem 267: 14157–14166PubMedGoogle Scholar
  160. Reha-Krantz LJ (1990) Genetic evidence for two protein domains and a potential new activity in bacteriophage T4 DNA polymerase. Genetics 124: 213–220PubMedGoogle Scholar
  161. Reha-Krantz LJ, Stocki S, Nonay RL, Dimayuga E, Goodrich LD, Konigsberg WH, Spicer EK (1991) DNA polymerization in the absence of exonucleolytic proofreading: in vivo and in vitro studies. Proc Natl Acad Sci USA 88: 2417–2421PubMedCrossRefGoogle Scholar
  162. Ridley RG, White JH, McAleese SM, Goman M, Alano P, de Vries E, Kilbey BJ (1991) DNA polymerase S: gene sequences from Plasmodium falciparum indicate that this enzyme is more highly conserved than DNA polymerase a. Nucleic Acids Res 19: 6731–6736PubMedCrossRefGoogle Scholar
  163. Roizman B (1982) The family herpesviridae: general description, taxonomy and classification. In: Roizman B (ed) The herpesviruses, vol 1. Plenum, New YorkGoogle Scholar
  164. Ruscitti T, Polayes DA, Karu AE, Linn S (1992) Selective immunoneutralization of the multiple activities of Escherichia coli DNA polymerase I supports the model for separate active sites and indicates a complex 5’ to 3’ exonuclease. J Biol Chem 267: 16806–16811PubMedGoogle Scholar
  165. Rush J, Konigsberg WH (1990) Photoaffinity labeling of the Klenow fragment with 8-azidodATP. J Biol Chem 265: 4821–4827PubMedGoogle Scholar
  166. Ruyechan WT (1983) The major herpes simplex virus DNA-binding protein hold single-stranded DNA in an extended configuration. J Virol 46: 661–666PubMedGoogle Scholar
  167. Schaffer PA, Aron GM, Biswal N, Benyesh-Melnick M (1973) Temperature-sensitive mutants of herpes simplex virus type 1: isolation, complementation and partial characterization. Virology 52: 57–71PubMedCrossRefGoogle Scholar
  168. Schnipper LE, Crumpacker CS (1980) Resistance of herpes simplex virus to acycloguanosine: the role of viral thymidine kinase and DNA polymerase loci. Proc Natl Acad Sci USA 77: 2270–2273PubMedCrossRefGoogle Scholar
  169. Segel IH (1975) Enzyme kinetics. Wiley-Interscience New YorkGoogle Scholar
  170. SenGupta DN, Zmudzka BZ, Kumar P, Cobianchi F, Skowronski J, Wilson SH (1986) Sequence of human DNA polymerase (3 mRNA obtained through cDNA cloning. Biochem Biophys Res Commun 136: 341–347PubMedCrossRefGoogle Scholar
  171. Sherman G, Gottlieb J, Challberg MD (1992) The UL8 subunit of the herpes simplex virus helicase-primase complex is required for efficient primer utilization. J Virol 66: 4884–4892PubMedGoogle Scholar
  172. Simon M, Giot L, Faye G (1991) The 3’ to 5’ exonuclease activity located in the DNA polymerase S subunit of Sacharomyces cerevisiae is required for accurate replication. EMBO J 10: 2165–2170PubMedGoogle Scholar
  173. Soengas MS, Esteban JA, Lâzaro JM, Bernad A, Blasco MA, Salas M, Blanco L (1992) Site-directed mutagenesis at the Exo III motif of X29 DNA polymerase; overlapping structural domains for the 3’-5’ exonuclease and strand-displacement activities. EMBO J 11: 4227–4237PubMedGoogle Scholar
  174. Spicer EK, Rush J, Fung C, Reha-Krantz LJ, Karam JD, Konigsberg WH (1988) Primary structure of T4 DNA polymerase: evolutionary relatedness of prokaryotic and eukaryotic DNA polymerases. J Biol Chem 263: 7478–7486PubMedGoogle Scholar
  175. Stow ND (1992) Herpes simplex virus type 1 origin-dependent DNA replication in insect cells using recombinant baculovirus. J Gen Virol 73: 313–321PubMedCrossRefGoogle Scholar
  176. Stow ND (1993) Sequences at the C-terminus of the herpes simplex virus type 1 UL30 protein are dispensable for DNA polymerase activity but not for viral origin-dependent DNA replication. Nucleic Acids Res 21: 87–92PubMedCrossRefGoogle Scholar
  177. Strick R (1993) Feinanalyse der katalytischen Proteindomänen des Enzyms HSV DNAPolymerase. Doctoral thesis, University of Heidelberg, HeidelbergGoogle Scholar
  178. Strick R, Knopf CW (1992) Improved band shift assay for the simultaneous analysis of protein-DNA interactions and enzymatic functions of DNA polymerases. FEBS Lett 300: 141–144PubMedCrossRefGoogle Scholar
  179. Telford EA, Watson MS, McBride KE, Davison AJ (1992) The DNA sequence of equine herpesvirus 1. EMBL Data library, HeidelbergGoogle Scholar
  180. Tenney DJ, Micheletti PA, Stevens JT, Hamatake RK, Matthews JT, Sanchez AR, Hurlburt WW, Bifano M, Cordingley MG (1993) Mutations in the C terminus of herpes simplex virus type 1 DNA polymerase can affect binding and stimulation by its accessory protein UL42 without affecting basal polymerase activity. J Virol 67: 543–547PubMedGoogle Scholar
  181. Teo IA, Griffin BE, Jones MD (1991) Characterization of the DNA polymerase gene of human herpesvirus 6. J Virol 65: 4670–4680PubMedGoogle Scholar
  182. Thomas MS, Banks LM, Purifoy DJM, Powell KL (1988) Production of antibodies of predetermined specificity against herpes simplex virus DNA polymerase and their use in characterization of the enzyme. J Virol 62: 1550–1557PubMedGoogle Scholar
  183. Thomas MS, Gao M, Knipe DM, Powell KL (1992) Association between the herpes simplex virus major DNA-binding protein and alkaline nuclease. J Virol 66: 1152–1161PubMedGoogle Scholar
  184. Tsurumi T, Maeno K, Nishiyama Y (1987) Nucleotide sequence of the DNA polymerase gene of herpes simplex virus type 2 and comparison with the type 1 counterpart. Gene 52: 129–137PubMedCrossRefGoogle Scholar
  185. Vaughan PJ, Purifoy DJM, Powell KL (1985) DNA-binding protein associated with herpes simplex virus DNA polymerase. J Virol 53: 501–508PubMedGoogle Scholar
  186. Wallace HM, Baybutt HN, Pearson CK, Keir HM (1980) The effect of polyamines on herpes simplex virus type 1 DNA polymerase purified from infected baby hamster kidney cells (BHK-21/C13). J Gen Virol 49: 387–400CrossRefGoogle Scholar
  187. Wang TS-F (1991) Eukaryotic DNA polymerases. Annu Rev Biochem 60: 513–552PubMedCrossRefGoogle Scholar
  188. Wang Y, Hall JD (1990) Characterization of a major DNA-binding domain in the herpes simplex virus type 1 DNA-binding protein (ICP8). J Virol 64: 2082–2089PubMedGoogle Scholar
  189. Wang Y, Woodward S, Hall JD (1992) Use of suppressor analysis to identify DNA polymerase mutations in herpes simplex virus which affect deoxynucleoside triphosphate substrate specificity. J Virol 66: 1814–1816PubMedGoogle Scholar
  190. Weissbach A, Hong A-CL, Aucker J, Muller R (1973) Characterization of herpes simplex virus-induced deoxyribonucleic acid polymerase. J Biol Chem 248: 6270–6277PubMedGoogle Scholar
  191. Weisshart K (1989) Kartierung and Expression der HSV-1 ANG DNA Polymerase. Doctoral thesis, University of Heidelberg, HeidelbergGoogle Scholar
  192. Weisshart K, Knopf CW (1988) The herpes simplex virus type I DNA polymerase. Polypeptide structure and antigenic domains. Eur J Biochem 174: 707–716PubMedCrossRefGoogle Scholar
  193. Weisshart K, Kuo AA, Painter GP, Wright LL, Furman PA, Coen DM (1993) Conformational changes induced in herpes simplex virus DNA polymerase upon DNA binding. Proc Natl Acad Sci USA 90: 1028–1032PubMedCrossRefGoogle Scholar
  194. Weller SK, Aschman DP, Sacks WR, Coen DM, Schaffer PA (1983) Genetic analysis of temperature-sensitive mutants of HSV-1: the combined use of complementation and physical mapping for cistron assignment. Virology 130: 290–305PubMedCrossRefGoogle Scholar
  195. Weller SK, Seghatoleslami MR, Shao L, Rowse D, Carmicheal EP (1990) The herpes simplex virus type 1 alkaline nuclease is not essential for viral DNA synthesis: isolation and characterization of a lac Z insertion mutant. J Gen Virol 71: 2941–2952PubMedCrossRefGoogle Scholar
  196. Wong SW, Wahl AF, Yuan P-M, Arai N, Pearson BE, Arai K, Korn D, Hunkapiller MW, Wang TS-F (1988) Human DNA polymerase a gene expression is cell proliferation dependent and its primary structure is similar to both prokaryotic and eukaryotic replicative DNA polymerases. EMBO J 7: 37–47PubMedGoogle Scholar
  197. Wu CA, Nelson NJ, McGeoch DJ, Challberg MD (1988) Identification of herpes simplex virus type 1 genes required for origin-dependent DNA synthesis. J Virol 62: 435–443PubMedGoogle Scholar
  198. Yadav PNS, Yadav JS, Modak JM (1992) A molecular model of the complete three-dimensional structure of the Klenow fragment of Escherichia coli DNA polymerase I: binding of the dNTP substrate and template-primer. Biochemistry 31: 2879–2886PubMedCrossRefGoogle Scholar
  199. Yager DR, Coen DM (1988) Analysis of the transcipt of the herpes simplex virus DNA polymerase genes provides evidence that polymerase expression is inefficient at the level of translation. J Viral 62: 2007–2015Google Scholar
  200. Yager DR, Marcy AI, Coen DM (1990) Translational regulation of herpes simplex virus DNA polymerase. J Virol 64: 2217–2225PubMedGoogle Scholar
  201. Yang C-L, Chang L-S, Zhang P, Hao H, Zhu L, Toomey NL, Lee MYWT (1992) Molecular cloning of the cDNA for the catalytic subunit of human DNA polymerase 6. Nucleic Acids Res 20: 735–745PubMedCrossRefGoogle Scholar
  202. Young MC, Reddy MK, von Hippel PH (1992) Structure and function of the bacteriophage T4 DNA polymerase holoenzyme. Biochemistry 31: 8675–8690PubMedCrossRefGoogle Scholar
  203. Zhang J, Chung DW, Tan CK, Downey KM, So AG, Davie EW (1991) Primary structure of the catalytic subunit of calf thymus DNA polymerase delta: sequence similarities with other DNA polymerases. Biochemistry 30: 11742–11750PubMedCrossRefGoogle Scholar
  204. Zmudzka BZ, SenGupta D, Matsukage A, Kumar P, Wilson SH (1986) Structure of rat DNA polymerase ß revealed by partial amino acid sequencing and eDNA cloning. Proc Natl Acad Sci USA 83: 5106–5110PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • Charles W. Knopf
    • 1
  • Reiner Strick
    • 1
  1. 1.Angewandte TumorvirologieDeutsches KrebsforschungszentrumHeidelbergGermany

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