Unbiased Mutagenesis of MHV68 LANA Reveals a DNA-Binding Domain Required for LANA Function In Vitro and In Vivo

PLoS Pathogens

Volumn 8, Issue 9, 2012, Pages

  Paden, Clinton R ^a,b   Forrest, J Craig ^c   Tibbetts, Scott A ^d   Speck, Samuel H ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b EMORY UNIVERSITY   (United States)

^c UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^d UNIVERSITY OF FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DEOXYRIBONUCLEASE I; LATENCY ASSOCIATED NUCLEAR ANTIGEN;

ANIMAL CELL; ARTICLE; DNA BINDING; GAMMAHERPESVIRINAE; IN VITRO STUDY; IN VIVO STUDY; MURINE GAMMA HERPES VIRUS 68; MUTAGENESIS; NONHUMAN; PHENOTYPE; PROTEIN DNA BINDING; PROTEIN FUNCTION; VIRUS GENOME; VIRUS REPLICATION;

ANIMALS; ANTIGENS, VIRAL; DNA; DNA-BINDING PROTEINS; GAMMAHERPESVIRINAE; GENE EXPRESSION REGULATION, VIRAL; HEK293 CELLS; HERPESVIRIDAE INFECTIONS; HUMANS; MICE; MUTAGENESIS; NIH 3T3 CELLS; NUCLEAR PROTEINS; PROTEIN INTERACTION DOMAINS AND MOTIFS; REPRESSION, PSYCHOLOGY; TERMINAL REPEAT SEQUENCES;

HERPESVIRIDAE; HUMAN HERPESVIRUS 8; MURINAE; RODENTIA;

EID: 84866927962     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1002906     Document Type: Article

References (72)

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865-1869.
2. Moore PS, (2000) The emergence of Kaposi's sarcoma-associated herpesvirus (Human Herpesvirus 8). N Eng J Med 343: 1411-1413.
3. Wen KW, Damania B, (2010) Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289: 140-150.
4. Kiyotaki M, Desrosiers RC, Letvin NL, (1986) Herpesvirus saimiri strain 11 immortalizes a restricted marmoset T8 lymphocyte subpopulation in vitro. J Exp Med 164: 926-931.
5. Sunil-Chandra NP, Arno J, Fazakerley J, Nash AA, (1994) Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am J Pathol 145: 818-826.
6. Liang X, Paden CR, Morales FM, Powers RP, Jacob J, et al. (2011) Murine gamma-herpesvirus immortalization of fetal liver-derived B cells requires both the viral cyclin D homolog and latency-associated nuclear antigen. PLoS Pathog 7: e1002220.
7. Melendez L, Hunt R, Daniel M, Blake BJ, Garcia F, (1971) Acute lymphocytic leukemia in owl monkeys inoculated with herpesvirus saimiri. Science 171: 1161-1163.
8. Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, et al. (1996) Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 335: 233-241.
9. Parravicini C, Chandran B, Corbellino M, Berti E, Paulli M, et al. (2000) Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am J Pathol 156: 743-749.
10. Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, et al. (1996) KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med 2: 925-928.
11. Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, et al. (1996) The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med 2: 918-924.
12. Friborg J Jr, Kong W, Hottiger MO, Nabel GJ, (1999) p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402: 889-894.
13. Sarid R, Wiezorek JS, Moore PS, Chang Y, (1999) Characterization and cell cycle regulation of the major Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter. J Virol 73: 1438-1446.
14. Verma SC, Lan K, Robertson E, (2007) Structure and function of latency-associated nuclear antigen. Curr Top Microbiol Immunol 312: 101-136.
15. Ballestas ME, Chatis PA, Kaye KM, (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284: 641-644.
16. Garber AC, Shu MA, Hu J, Renne R, (2001) DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75: 7882-7892.
17. Cotter MA 2nd, Subramanian C, Robertson ES, (2001) The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen binds to specific sequences at the left end of the viral genome through its carboxy-terminus. Virology 291: 241-259.
18. Ballestas ME, Kaye KM, (2001) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol 75: 3250-3258.
19. Collins CM, Medveczky PG, (2002) Genetic requirements for the episomal maintenance of oncogenic herpesvirus genomes. Adv Cancer Res 84: 155-174.
20. Fejér G, Medveczky MM, Horvath E, Lane B, Chang Y, et al. (2003) The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts preferentially with the terminal repeats of the genome in vivo and this complex is sufficient for episomal DNA replication. J Gen Virol 84: 1451-1462.
21. Paden CR, Forrest JC, Moorman NJ, Speck SH, (2010) Murine gammaherpesvirus 68 LANA is essential for virus reactivation from splenocytes but not long-term carriage of viral genome. J Virol 84: 7214-7224.
22. Hu J, Garber AC, Renne R, (2002) The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus supports latent DNA replication in dividing cells. J Virol 76: 11677-11687.
23. Han SJ, Hu J, Pierce B, Weng Z, Renne R, (2010) Mutational analysis of the latency-associated nuclear antigen DNA-binding domain of Kaposi's sarcoma-associated herpesvirus reveals structural conservation among gammaherpesvirus origin-binding proteins. J Gen Virol 91: 2203-2215.
24. Renne R, Barry C, Dittmer D, Compitello N, Brown PO, et al. (2001) Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75: 458-468.
25. Srinivasan V, Komatsu T, Ballestas ME, Kaye KM, (2004) Definition of sequence requirements for latency-associated nuclear antigen 1 binding to Kaposi's sarcoma-associated herpesvirus DNA. J Virol 78: 14033-14038.
26. Komatsu T, Ballestas ME, Barbera AJ, Kelley-Clarke B, Kaye KM, (2004) KSHV LANA1 binds DNA as an oligomer and residues N-terminal to the oligomerization domain are essential for DNA binding, replication, and episome persistence. Virology 319: 225-236.
27. Forrest JC, Paden CR, Allen RD 3rd, Collins J, Speck SH, (2007) ORF73-null murine gammaherpesvirus 68 reveals roles for mLANA and p53 in virus replication. J Virol 81: 11957-11971.
28. Moorman NJ, Willer DO, Speck SH, (2003) The gammaherpesvirus 68 latency-associated nuclear antigen homolog is critical for the establishment of splenic latency. J Virol 77: 10295-10303.
29. Allen RD 3rd, Dickerson S, Speck SH, (2006) Identification of spliced gammaherpesvirus 68 LANA and v-cyclin transcripts and analysis of their expression in vivo during latent infection. J Virol 80: 2055-2062.
30. Garber AC, Hu J, Renne R, (2002) Latency-associated nuclear antigen (LANA) cooperatively binds to two sites within the terminal repeat, and both sites contribute to the ability of LANA to suppress transcription and to facilitate DNA replication. J Biol Chem 277: 27401-27411.
31. Virgin HWt, Latreille P, Wamsley P, Hallsworth K, Weck KE, et al. (1997) Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71: 5894-5904.
32. Coleman HM, Efstathiou S, Stevenson PG, (2005) Transcription of the murine gammaherpesvirus 68 ORF73 from promoters in the viral terminal repeats. J Gen Virol 86: 561-574.
33. Kelley LA, Sternberg MJ, (2009) Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4: 363-371.
34. Bochkarev A, Barwell JA, Pfuetzner RA, Furey W Jr, Edwards AM, et al. (1995) Crystal structure of the DNA-binding domain of the Epstein-Barr virus origin-binding protein EBNA 1. Cell 83: 39-46.
35. Dittmer D, Lagunoff M, Renne R, Staskus K, Haase A, et al. (1998) A cluster of latently expressed genes in Kaposi's sarcoma-associated herpesvirus. J Virol 72: 8309-8315.
36. Grundhoff A, Ganem D, (2003) The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus permits replication of terminal repeat-containing plasmids. J Virol 77: 2779-2783.
37. Cruickshank J, Shire K, Davidson AR, Edwards AM, Frappier L, (2000) Two domains of the epstein-barr virus origin DNA-binding protein, EBNA1, orchestrate sequence-specific DNA binding. J Biol Chem 275: 22273-22277.
38. Ambinder RF, Mullen MA, Chang YN, Hayward GS, Hayward SD, (1991) Functional domains of Epstein-Barr virus nuclear antigen EBNA-1. J Virol 65: 1466-1478.
39. Warming S, Costantino N, Court DL, Jenkins NA, Copeland NG, (2005) Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33: e36.
40. Collins CM, Boss JM, Speck SH, (2009) Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83: 6484-6493.
41. Fowler P, Marques S, Simas JP, Efstathiou S, (2003) ORF73 of murine herpesvirus-68 is critical for the establishment and maintenance of latency. J Gen Virol 84: 3405-3416.
42. Husain SM, Usherwood EJ, Dyson H, Coleclough C, Coppola MA, et al. (1999) Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8+ T lymphocytes. Proc Natl Acad Sci U S A 96: 7508.
43. Wen KW, Dittmer DP, Damania B, (2009) Disruption of LANA in rhesus rhadinovirus generates a highly lytic recombinant virus. J Virol 83: 9786-9802.
44. Krithivas A, Young DB, Liao G, Greene D, Hayward SD, (2000) Human herpesvirus 8 LANA interacts with proteins of the mSin3 corepressor complex and negatively regulates Epstein-Barr virus gene expression in dually infected PEL cells. J Virol 74: 9637-9645.
45. Li Q, Zhou F, Ye F, Gao SJ, (2008) Genetic disruption of KSHV major latent nuclear antigen LANA enhances viral lytic transcriptional program. Virology 379: 234-244.
46. Cheng BYH, Zhi J, Santana A, Khan S, Salinas E, et al. (2012) Tiled Microarray Identification of Novel Viral Transcript Structures and Distinct Transcriptional Profiles During Two Modes of Productive Murine Gammaherpesvirus 68 Infection. J Virol 86: 4340-57.
47. Rawlins DR, Milman G, Hayward SD, Hayward GS, (1985) Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region. Cell 42: 859-868.
48. Inoue N, Harada S, Honma T, Kitamura T, Yanagi K, (1991) The domain of Epstein-Barr virus nuclear antigen 1 essential for binding to oriP region has a sequence fitted for the hypothetical basic-helix-loop-helix structure. Virology 182: 84-93.
49. Bochkarev A, Barwell JA, Pfuetzner RA, Bochkareva E, Frappier L, et al. (1996) Crystal structure of the DNA-binding domain of the Epstein-Barr virus origin-binding protein, EBNA1, bound to DNA. Cell 84: 791-800.
50. Goldsmith K, Bendell L, Frappier L, (1993) Identification of EBNA1 amino acid sequences required for the interaction of the functional elements of the Epstein-Barr virus latent origin of DNA replication. J Virol 67: 3418-3426.
51. Verma SC, Choudhuri T, Kaul R, Robertson ES, (2006) Latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus interacts with origin recognition complexes at the LANA binding sequence within the terminal repeats. J Virol 80: 2243-2256.
52. Verma SC, Lan K, Choudhuri T, Cotter MA, Robertson ES, (2007) An autonomous replicating element within the KSHV genome. Cell Host Microbe 2: 106-118.
53. Shamay M, Krithivas A, Zhang J, Hayward SD, (2006) Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA. Proc Natl Acad Sci U S A 103: 14554-14559.
54. Sun R, Spain TA, Lin SF, Miller G, (1997) Sp1 binds to the precise locus of end processing within the terminal repeats of Epstein-Barr virus DNA. J Virol 71: 6136-6143.
55. Barbera AJ, Ballestas ME, Kaye KM, (2004) The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 N terminus is essential for chromosome association, DNA replication, and episome persistence. J Virol 78: 294-301.
56. Kelley-Clarke B, Ballestas ME, Srinivasan V, Barbera AJ, Komatsu T, et al. (2007) Determination of Kaposi's sarcoma-associated herpesvirus C-terminal latency-associated nuclear antigen residues mediating chromosome association and DNA binding. J Virol 81: 4348-4356.
57. You J, Srinivasan V, Denis GV, Harrington WJ Jr, Ballestas ME, et al. (2006) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 80: 8909-8919.
58. Jin XW, Speck SH, (1992) Identification of critical cis elements involved in mediating Epstein-Barr virus nuclear antigen 2-dependent activity of an enhancer located upstream of the viral BamHI C promoter. J Virol 66: 2846-2852.
59. Tierney RJ, Kirby HE, Nagra JK, Desmond J, Bell AI, et al. (2000) Methylation of transcription factor binding sites in the Epstein-Barr virus latent cycle promoter Wp coincides with promoter down-regulation during virus-induced B-cell transformation. J Virol 74: 10468-10479.
60. Jansson A, Masucci M, Rymo L, (1992) Methylation of discrete sites within the enhancer region regulates the activity of the Epstein-Barr virus BamHI W promoter in Burkitt lymphoma lines. J Virol 66: 62-69.
61. Fakhari FD, Jeong JH, Kanan Y, Dittmer DP, (2006) The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest 116: 735-742.
62. Jeong JH, Hines-Boykin R, Ash JD, Dittmer DP, (2002) Tissue specificity of the Kaposi's sarcoma-associated herpesvirus latent nuclear antigen (LANA/orf73) promoter in transgenic mice. J Virol 76: 11024-11032.
63. Kirchmaier AL, Sugden B, (1997) Dominant-negative inhibitors of EBNA-1 of Epstein-Barr virus. J Virol 71: 1766-1775.
64. Li N, Thompson S, Schultz DC, Zhu W, Jiang H, et al. (2010)Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening. PLoS One 5: e10126.
65. Thompson S, Messick T, Schultz DC, Reichman M, Lieberman PM, (2010) Development of a high-throughput screen for inhibitors of Epstein-Barr virus EBNA1. J Biomol Screen 15: 1107-1115.
66. van Dyk LF, Virgin HWt, Speck SH, (2000) The murine gammaherpesvirus 68 v-cyclin is a critical regulator of reactivation from latency. J Virol 74: 7451-7461.
67. Jeong JH, Orvis J, Kim JW, McMurtrey CP, Renne R, et al. (2004) Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Biol Chem 279: 16822-16831.
68. Lee W, Mitchell P, Tjian R, (1987) Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 49: 741-752.
69. Flemington E, Speck SH, (1990) Identification of phorbol ester response elements in the promoter of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol 64: 1217-1226.
70. Upton JW, Speck SH, (2006) Evidence for CDK-dependent and CDK-independent functions of the murine gammaherpesvirus 68 v-cyclin. J Virol 80: 11946-11959.
71. Weck KE, Barkon ML, Yoo LI, Speck SH, Virgin HI, (1996) Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70: 6775-6780.
72. Weck KE, Kim SS, Virgin HI, Speck SH, (1999) Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J Virol 73: 3273-3283.