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Human cytomegalovirus riding the cell cycle

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Abstract

Human cytomegalovirus (HCMV) infection modulates the host cell cycle to create an environment that is optimal for viral gene expression, DNA replication, and production of infectious virus. The virus mostly infects quiescent cells and thus must push the cell into G1 phase of the cell cycle to co-opt the cellular mechanisms that could be used for DNA synthesis. However, at the same time, cellular functions must be subverted such that synthesis of viral DNA is favored over that of the host. The molecular mechanisms by which this is accomplished include altered RNA transcription, changes in the levels and activity of cyclin-dependent kinases, and other proteins involved in cell cycle control, posttranslational modifications of proteins, modulation of protein stability through targeted effects on the ubiquitin–proteasome degradation pathway, and movement of proteins to different cellular locations. When the cell is in the optimal G0/G1 phase, multiple signaling pathways are altered to allow rapid induction of viral gene expression once negative factors have been eliminated. For the most part, the cell cycle will stop prior to initiation of host cell DNA synthesis (S phase), although many cell cycle proteins characteristic of the S/G2/M phase accumulate. The environment of a cell progressing through the cell cycle and dividing is not favorable for viral replication, and HCMV has evolved ways to sense whether cells are in S/G2 phase, and if so, to prevent initiation of viral gene expression until the cells cycle back to G1. A major target of HCMV is the anaphase-promoting complex E3 ubiquitin ligase, which is responsible for the ubiquitination and subsequent degradation of cyclins A and B and other cell cycle proteins at specific phases in the cell cycle. This review will discuss the effects of HCMV infection on cell cycle regulatory pathways, with the focus on selected viral proteins that are responsible for these effects.

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References

  1. Mocarski ES, Shenk T, Pass RF (2007) Cytomegaloviruses. In: Knipe DM, Howley PM (eds) Fields virology, vol 2, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2701–2772

    Google Scholar 

  2. Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116:221–234

    Article  CAS  PubMed  Google Scholar 

  3. Satyanarayana A, Kaldis P (2009) Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 28:2925–2939

    Article  CAS  PubMed  Google Scholar 

  4. Teixeira LK, Reed SI (2013) Ubiquitin ligases and cell cycle control. Annu Rev Biochem 82:387–414

    Article  CAS  PubMed  Google Scholar 

  5. Blow JJ, Dutta A (2005) Preventing re-replication of chromosomal DNA. Nat Rev Mol Cell Biol 6:476–486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Bottazzi ME, Buzzai M, Zhu X, Desdouets C, Brechot C, Assoian RK (2001) Distinct effects of mitogens and actin cytoskeleton on CREB and pocket protein phosphorylation control the extent and timing of cyclin A promoter activity. Mol Cell Biol 21:7607–7616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Desdouets C, Matesic G, Molina CA, Foulkes NS, Sassone-Corsi P, Bréchot C, Sobszak-Thepot J (1995) Cell cycle regulation of cyclin A gene expression by the cyclic AMP transcription factors CREB and CREM. Mol Cell Biol 15:3301–3309

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Henglein B, Chenivesse X, Wang J, Eick D, Bréchot C (1994) Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc Natl Acad Sci USA 91:5490–5494

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Zwicker J, Muller R (1997) Cell-cycle regulation of gene expression by transcriptional repression. Trends Genet 13:3–6

    Article  CAS  PubMed  Google Scholar 

  10. Glotzer M, Murray AW, Kirschner MW (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349:132–138

    Article  CAS  PubMed  Google Scholar 

  11. Tessari MA, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno C, Caretti G, Imbriano C, Mantovani R, Sal GD et al (2003) Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2. Mol Cell Biol 23:9104–9116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Schulze A, Zerfass K, Spitkovsky D, Middendorp S, Berges J, Helin K, Jansen-Dürr P, Henglein B (1995) Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci USA 92:11264–11268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zwicker J, Lucibello FC, Wolfraim LA, Gross C, Truss M, Engeland K, Muller R (1995) Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J 14:4514–4522

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Nishitani H, Lygerou Z (2002) Control of DNA Replication. Genes Cells 7:523–534

    Article  CAS  PubMed  Google Scholar 

  15. Machida YJ, Hamlin JL, Dutta A (2005) Right place, right time, and only once: replication initiation in metazoans. Cell 123:13–24

    Article  CAS  PubMed  Google Scholar 

  16. Millar JBA, Russell P (1992) The cdc25 M-phase inducer: an unconventional protein phosphatase. Cell 68:407–410

    Article  CAS  PubMed  Google Scholar 

  17. McGarry TJ, Kirschner MW (1998) Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93:1043–1053

    Article  CAS  PubMed  Google Scholar 

  18. Brandeis M, Hunt T (1996) The proteolysis of mitotic cyclins in mammalian cells persists from the end of mitosis until the onset of S phase. EMBO J 15:5280–5289

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Lukas J, Lukas C, Bartek J (2004) Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time. DNA Repair 3:997–1007

    Article  CAS  PubMed  Google Scholar 

  20. Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–2262

    Article  CAS  PubMed  Google Scholar 

  21. Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF (2014) Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife 3:e02872

    Article  PubMed Central  Google Scholar 

  22. Slee EA, O’Connor DJ, Lu X (2004) To die or not to die: how does p53 decide? Oncogene 23:2809–2818

    Article  CAS  PubMed  Google Scholar 

  23. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev 2:594–604

    Article  CAS  Google Scholar 

  24. Lavin MF, Gueven N (2006) The complexity of p53 stabilization and activation. Cell Death Differ 13:941–950

    Article  CAS  PubMed  Google Scholar 

  25. Bresnahan WA, Boldogh I, Thompson EA, Albrecht T (1996) Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1. Virology 224:156–160

    Article  Google Scholar 

  26. Dittmer D, Mocarski ES (1997) Human cytomegalovirus infection inhibits G1/S transition. J Virol 71:1629–1634

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Jault FM, Jault J-M, Ruchti F, Fortunato EA, Clark C, Corbeil J, Richman DD, Spector DH (1995) Cytomegalovirus infection induces high levels of cyclins, phosphorylated RB, and p53, leading to cell cycle arrest. J Virol 69:6697–6704

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Lu M, Shenk T (1996) Human cytomegalovirus infection inhibits cell cycle progression at multiple points, including the transition from G1 to S. J Virol 70:8850–8857

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Salvant BS, Fortunato EA, Spector DH (1998) Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription. J Virol 72:3729–3741

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Wiebusch L, Hagemeier C (1999) Human cytomegalovirus 86-kilodalton IE2 protein blocks cell cycle progression in G1. J Virol 73:9274–9283

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Wiebusch L, Hagemeier C (2001) The human cytomegalovirus immediate early 2 protein dissociates cellular DNA synthesis from cyclin dependent kinase activation. EMBO J 20:1086–1098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Hertel L, Mocarski ES (2004) Global analysis of host cell gene expression late during cytomegalovirus infection reveals extensive dysregulation of cell cycle gene expression and induction of pseudomitosis independent of US28 function. J Virol 78(21):11988–12011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Challacombe JF, Rechtsteiner A, Gottardo R, Rocha LM, Browne EP, Shenk T, Altherr MR, Brettin TS (2004) Evaluation of the host transcriptional response to human cytomegalovirus infection. Physiol Genomics 18:51–62

    Article  CAS  PubMed  Google Scholar 

  34. Sanchez V, McElroy AK, Spector DH (2003) Mechanisms governing maintenance of cdk1/cyclin B1 kinase activity in cells infected with human cytomegalovirus. J Virol 77:13214–13224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Shlapobersky M, Sanders R, Clark C, Spector DH (2006) Repression of HMGA2 gene expression by human cytomegalovirus involves the IE2 86-kilodalton protein and is necessary for efficient viral replication and inhibition of cyclin A transcription. J Virol 80:9951–9961

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Caffarelli N, Fehr AR, Yu D (2013) Cyclin A degradation by primate cytomegalovirus protein pUL21a counters its innate restriction of virus replication. PLoS Pathog 9(12):e1003825

    Article  PubMed Central  PubMed  Google Scholar 

  37. Eifler M, Uecker R, Weisbach H, Bogdanow B, Richter E, Konig L, Vetter B, Lenac-Rovis T, Jonjic S, Neitzel H et al (2014) PUL21a-Cyclin A2 interaction is required to protect human cytomegalovirus-infected cells from the deleterious consequences of mitotic entry. PLoS Pathog 10(10):e1004514

    Article  PubMed Central  PubMed  Google Scholar 

  38. Casavant NC, Luo MH, Rosenke K, Winegardner T, Zurawska A, Fortunato EA (2006) Potential role for p53 in the permissive life cycle of human cytomegalovirus. J Virol 80:8390–8401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Fortunato EA, Spector DH (1998) p53 and RPA are sequestered in viral replication centers in the nuclei of cells infected with human cytomegalovirus. J Virol 72:2033–2039

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Muganda P, Mendoza O, Hernandez J, Qian Q (1994) Human cytomegalovirus elevates levels of the cellular protein p53 in infected fibroblasts. J Virol 68:8028–8034

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Chen Z, Knutson E, Kurosky A, Albrecht T (2001) Degradation of p21cip1 in cells productively infected with human cytomegalovirus. J Virol 75:3613–3625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Biswas N, Sanchez V, Spector DH (2003) Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication. J Virol 77:2369–2376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. McElroy AK, Dwarakanath RS, Spector DH (2000) Dysregulation of cyclin E gene expression in human cytomegalovirus-infected cells requires viral early gene expression and is associated with changes in the Rb-related protein p130. J Virol 74:4192–4206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Grey F, Tirabassi R, Meyers H, Wu G, McWeeney S, Hook L, Nelson JA (2010) A viral microRNA down-regulates multiple cell cycle genes through mRNA 5’UTRs. PLoS Pathog 6:e1000967

    Article  PubMed Central  PubMed  Google Scholar 

  45. Lu M, Shenk T (1999) Human cytomegalovirus UL69 protein induces cells to accumulate in G1 phase of the cell cycle. J Virol 73:676–683

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Hayashi ML, Blankenship C, Shenk T (2000) Human cytomegalovirus UL69 is required for efficient accumulation of infected cells in the G1 phase of the cell cycle. Proc Natl Acad Sci USA 97(6):2692–2696

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Ayoubi TA, Jansen E, Meulemans SM, Van de Ven WJ (1999) Regulation of HMGIC expression: an architectural transcription factor involved in growth control and development. Oncogene 18:5076–5087

    Article  CAS  PubMed  Google Scholar 

  48. Lischka P, Toth Z, Thomas M, Mueller R, Stamminger T (2006) The UL69 transactivator protein of human cytomegalovirus interacts with DEXD/H-Box RNA helicase UAP56 to promote cytoplasmic accumulation of unspliced RNA. Mol Cell Biol 26(5):1631–1643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Cygnar D, Hagemeier S, Kronemann D, Bresnahan WA (2012) The cellular protein SPT6 is required for efficient replication of human cytomegalovirus. J Virol 86:2011–2020

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Dunn C, Chalupny NJ, Sutherland CL, Dosch S, Sivakumar PV, Johnson DC, Cosman D (2003) Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. J Exp Med 197:1427–1439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Bresnahan WA, Hultman GE, Shenk T (2000) Replication of wild-type and mutant human cytomegalovirus in life-extended human diploid fibroblasts. J Virol 74:10816–10818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Kalejta RF, Bechtel JT, Shenk T (2003) Human cytomegalovirus pp71 stimulates cell cycle progression by inducing the proteasome-dependent degradation of the retinoblastoma family of tumor suppressors. Mol Cell Biol 23:1885–1895

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Cantrell SR, Bresnahan WA (2005) Interaction between the human cytomegalovirus UL82 gene product (pp71) and hDaxx regulates immediate-early gene expression and viral replication. J Virol 79:7792–7802

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Ishov AM, Vladimirova OV, Maul GG (2002) Daxx-mediated accumulation of human cytomegalovirus tegument protein pp71 at ND10 facilitates initiation of viral infection at these nuclear domains. J Virol 76(15):7705–7712

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Hofmann H, Sindre H, Stamminger T (2002) Functional interaction between the pp71 protein of human cytomegalovirus and the PML-interacting protein human Daxx. J Virol 76(11):5769–5783

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Marshall KR, Rowley KV, Rinaldi A, Nicholson IP, Ishov AM, Maul GG, Preston CM (2002) Activity and intracellular localization of the human cytomegalovirus protein pp71. J Gen Virol 83:1601–1612

    CAS  PubMed  Google Scholar 

  57. Saffert RT, Kalejta RF (2006) Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression. J Virol 80:3863–3871

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Lukashchuk V, McFarlane S, Everett RD, Preston CM (2008) Human cytomegalovirus protein pp71 displaces the chromatin-associated factor ATRX from nuclear domain 10 at early stages of infection. J Virol 82:12543–12554

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Preston CM, Nicholl MJ (2006) Role of the cellular protein hDaxx in human cytomegalovirus immediate-early gene expression. J Gen Virol 87:1113–1121

    Article  CAS  PubMed  Google Scholar 

  60. Hwang J, Kalejta RF (2007) Proteasome-dependent, ubiquitin-independent degradation of Daxx by the viral pp71 protein in human cytomegalovirus-infected cells. Virology 367:334–338

    Article  CAS  PubMed  Google Scholar 

  61. Castillo JP, Yurochko A, Kowalik TF (2000) Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 74:8028–8037

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Castillo JP, Frame FM, Rogoff HA, Pickering MT, Yurochko AD, Kowalik TF (2005) Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J Virol 79(17):11467–11475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Speir E, Modali R, Huang E-S, Leon MB, Sahwl F, Finkel T, Epstein SE (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265:391–394

    Article  CAS  PubMed  Google Scholar 

  64. Bonin LR, McDougall JK (1997) Human cytomegalovirus IE2 86-kilodalton protein binds p53 but does not abrogate G1 checkpoint function. J Virol 71:5861–5870

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Hagemeier C, Caswell R, Hayhurst G, Sinclair J, Kouzarides T (1994) Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J 13:2897–2903

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Sommer MH, Scully AL, Spector DH (1994) Trans-activation by the human cytomegalovirus IE2 86 kDa protein requires a domain that binds to both TBP and RB. J Virol 68:6223–6231

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Fortunato EA, Sommer MH, Yoder K, Spector DH (1997) Identification of domains within the human cytomegalovirus major immediate-early 86-kilodalton protein and the retinoblastoma protein required for physical and functional interaction with each other. J Virol 71:8176–8185

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Song Y-J, Stinski MF (2002) Effect of the human cytomegalovirus IE86 protein on expression of E2F responsive genes: a DNA microarray analysis. Proc Natl Acad Sci USA 99:2836–2841

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Wiebusch L, Asmar J, Uecker R, Hagemeier C (2003) Human cytomegalovirus immediate-early protein 2 (IE2)-mediated activation of cyclin E is cell-cycle-independent and forces S-phase entry in IE2-arrested cells. J Gen Virol 84:51–60

    Article  CAS  PubMed  Google Scholar 

  70. Murphy EA, Streblow DN, Nelson JA, Stinski MF (2000) The human cytomegalovirus IE86 protein can block cell cycle progression after inducing transition into the S phase of the cell cycle. J Virol 74:7108–7118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Noris E, Zannetti C, Demurtas A, Sinclair J, De Andrea M, Gariglio M, Landolfo S (2002) Cell cycle arrest by human cytomegalovirus 86-kDa IE2 protein resembles premature senescence. J Virol 76(23):12135–12148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Song YJ, Stinski MF (2005) Inhibition of cell division by the human cytomegalovirus IE86 protein: role of the p53 pathway or cyclin-dependent kinase 1/cyclin B1. J Virol 79:2597–2603

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Poole E, Bain M, Teague L, Takei Y, Laskey R, Sinclair J (2012) The cellular protein MCM3AP is required for inhibition of cellular DNA synthesis by the IE86 protein of human cytomegalovirus. PLoS One 7(10):e45686

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Bresnahan WA, Albrecht T, Thompson EA (1998) The cyclin E promoter is activated by human cytomegalovirus 86-kDa immediate early protein. J Biol Chem 273:22075–22082

    Article  CAS  PubMed  Google Scholar 

  75. White EA, Spector DH (2005) Exon 3 of the human cytomegalovirus major immediate-early region is required for efficient viral gene expression and for cellular cyclin modulation. J Virol 79:7438–7452

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Ciechanover A (1994) The ubiquitin–proteasome proteolytic pathway. Cell 79:13–21

    Article  CAS  PubMed  Google Scholar 

  77. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    Article  CAS  PubMed  Google Scholar 

  78. Eguren M, Manchado E, Malumbres M (2011) Non-mitotic functions of the anaphase-promoting complex. Semin Cell Dev Biol 22(6):572–578

    Article  CAS  PubMed  Google Scholar 

  79. Fehr AR, Yu D (2013) Control the host cell cycle: viral regulation of the anaphase-promoting complex. J Virol 87(16):8818–8825

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Chang L, Zhang Z, Yang J, McLaughlin SH, Barford D (2014) Molecular architecture and mechanism of the anaphase-promoting complex. Nature 513(7518):388–393

    Article  CAS  PubMed  Google Scholar 

  81. Wiebusch L, Bach M, Uecker R, Hagemeier C (2005) Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation. Cell Cycle 4:1435–1439

    Article  CAS  PubMed  Google Scholar 

  82. Sanchez V, Spector DH (2006) Cyclin-dependent kinase activity is required for efficient expression and posttranslational modification of human cytomegalovirus proteins and for production of extracellular particles. J Virol 80:5886–5896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Wiebusch L, Uecker R, Hagemeier C (2003) Human cytomegalovirus prevents replication licensing by inhibiting MCM loading onto chromatin. EMBO Rep 4(1):42–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Tran K, Kamil JP, Coen DM, Spector DH (2010) Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. J Virol 84:10832–10843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Tran K, Mahr JA, Choi J, Teodoro JG, Green MR, Spector DH (2008) Accumulation of substrates of the anaphase-promoting complex (APC) during human cytomegalovirus infection is associated with the phosphorylation of Cdh1 and the dissociation and relocalization of the APC subunits. J Virol 82:529–537

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Fehr AR, Gualberto NC, Savaryn JP, Terhune SS, Yu D (2012) Proteasome-dependent disruption of the E3 ubiquitin ligase anaphase-promoting complex by HCMV protein pUL21a. PLoS Pathog 8:e1002789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Fortunato EA, Sanchez V, Yen JY, Spector DH (2002) Infection of cells with human cytomegalovirus during S phase results in a blockade to immediate-early gene expression that can be overcome by inhibition of the proteasome. J Virol 76:5369–5379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Zydek M, Hagemeier C, Wiebusch L (2010) Cyclin-dependent kinase activity controls the onset of the HCMV lytic cycle. PLoS Pathog 6:e1001096

    Article  PubMed Central  PubMed  Google Scholar 

  89. Zydek M, Uecker R, Tavalai N, Stamminger T, Hagemeier C, Wiebusch L (2011) General blockade of human cytomegalovirus immediate-early mRNA expression in the S/G2 phase by a nuclear, Daxx- and PML-independent mechanism. J Gen Virol 92:2757–2769

    Article  CAS  PubMed  Google Scholar 

  90. Sanchez V, McElroy AK, Yen J, Tamrakar S, Clark CL, Schwartz RA, Spector DH (2004) Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production. J Virol 78(20):11219–11232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Tamrakar S, Kapasi AJ, Spector DH (2005) Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7. J Virol 79:15477–15493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Kapasi AJ, Spector DH (2008) Inhibition of the cyclin-dependent kinases at the beginning of the human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome. J Virol 82:394–407

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Maul GG, Negorev D (2008) Differences between mouse and human cytomegalovirus interactions with their respective hosts at immediate early times of the replication cycle. Med Microbiol Immunol 197:241–249

    Article  PubMed  Google Scholar 

  94. Wiebusch L, Neuwirth A, Grabenhenrich L, Voigt S, Hagemeier C (2008) Cell cycle-independent expression of immediate-early gene 3 results in G1 and G2 arrest in murine cytomegalovirus-infected cells. J Virol 82:10188–10198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Oduro JD, Uecker R, Hagemeier C, Wiebusch L (2012) Inhibition of human cytomegalovirus immediate-early gene expression by cyclin A2-dependent kinase activity. J Virol 86(17):9369–9383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Bogdanow B, Weisbach H, von Einem J, Straschewski S, Voigt S, Winkler M, Hagemeier C, Wiebusch L (2013) Human cytomegalovirus tegument protein pp150 acts as a cyclin A2-CDK-dependent sensor of the host cell cycle and differentiation state. Proc Natl Acad Sci USA 110(43):17510–17515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Qian Z, Leung-Pineda V, Xuan B, Piwnica-Worms H, Yu D (2010) Human cytomegalovirus protein pUL117 targets the mini-chromosome maintenance complex and suppresses cellular DNA synthesis. PLoS Pathog 6:e1000814

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Research in the Spector laboratory was supported by NIH Grants CA073490 and AI0883991.

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  1. Department of Cellular and Molecular Medicine, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093-0712, USA

    Deborah H. Spector

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Correspondence to Deborah H. Spector.

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This article is part of the Special Issue on Cytomegalovirus.

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Spector, D.H. Human cytomegalovirus riding the cell cycle. Med Microbiol Immunol 204, 409–419 (2015). https://doi.org/10.1007/s00430-015-0396-z

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