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. 1997 Dec;71(12):9008–9015. doi: 10.1128/jvi.71.12.9008-9015.1997

Directed integration of minute virus of mice DNA into episomes.

J Corsini 1, J Tal 1, E Winocour 1
PMCID: PMC230201  PMID: 9371557

Abstract

Recent studies with adeno-associated virus (AAV) have shown that site-specific integration is directed by DNA sequence motifs that are present in both the viral replication origin and the chromosomal preintegration DNA and that specify binding and nicking sites for the viral regulatory Rep protein. This finding raised the question as to whether other parvovirus regulatory proteins might direct site-specific recombination with DNA targets that contain origin sequences functionally equivalent to those described for AAV. To investigate this question, active and inactive forms of the minute virus of mice (MVM) 3' replication origin, derived from a replicative-form dimer-bridge intermediate, were propagated in an Epstein-Barr virus-based shuttle vector which replicates as an episome in a cell-cycle-dependent manner in mammalian cells. Upon MVM infection of these cells, the infecting genome integrated into episomes containing the active-origin sequence reported to be efficiently nicked by the MVM regulatory protein NS1. In contrast, MVM did not integrate into episomes containing either the inactive form of the origin sequence reported to be inefficiently nicked by NS1 or the active form from which the NS1 consensus nick site had been deleted. The structure of the cloned MVM episomal recombinants displayed several features previously described for AAV episomal and chromosomal recombinants. The findings indicate that the rules which govern AAV site-specific recombination also apply to MVM and suggest that site-specific chromosomal insertions may be achievable with different autonomous parvovirus replicator proteins which recognize binding and nicking sites on the target DNA.

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Selected References

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  1. Astell C. R., Chow M. B., Ward D. C. Sequence analysis of the termini of virion and replicative forms of minute virus of mice DNA suggests a modified rolling hairpin model for autonomous parvovirus DNA replication. J Virol. 1985 Apr;54(1):171–177. doi: 10.1128/jvi.54.1.171-177.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Astell C. R., Gardiner E. M., Tattersall P. DNA sequence of the lymphotropic variant of minute virus of mice, MVM(i), and comparison with the DNA sequence of the fibrotropic prototype strain. J Virol. 1986 Feb;57(2):656–669. doi: 10.1128/jvi.57.2.656-669.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Astell C. R., Thomson M., Chow M. B., Ward D. C. Structure and replication of minute virus of mice DNA. Cold Spring Harb Symp Quant Biol. 1983;47(Pt 2):751–762. doi: 10.1101/sqb.1983.047.01.086. [DOI] [PubMed] [Google Scholar]
  4. Astell C. R., Thomson M., Merchlinsky M., Ward D. C. The complete DNA sequence of minute virus of mice, an autonomous parvovirus. Nucleic Acids Res. 1983 Feb 25;11(4):999–1018. doi: 10.1093/nar/11.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Balagúe C., Kalla M., Zhang W. W. Adeno-associated virus Rep78 protein and terminal repeats enhance integration of DNA sequences into the cellular genome. J Virol. 1997 Apr;71(4):3299–3306. doi: 10.1128/jvi.71.4.3299-3306.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baldauf A. Q., Willwand K., Mumtsidu E., Nüesch J. P., Rommelaere J. Specific initiation of replication at the right-end telomere of the closed species of minute virus of mice replicative-form DNA. J Virol. 1997 Feb;71(2):971–980. doi: 10.1128/jvi.71.2.971-980.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brownstein D. G., Smith A. L., Johnson E. A., Pintel D. J., Naeger L. K., Tattersall P. The pathogenesis of infection with minute virus of mice depends on expression of the small nonstructural protein NS2 and on the genotype of the allotropic determinants VP1 and VP2. J Virol. 1992 May;66(5):3118–3124. doi: 10.1128/jvi.66.5.3118-3124.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cater J. E., Pintel D. J. The small non-structural protein NS2 of the autonomous parvovirus minute virus of mice is required for virus growth in murine cells. J Gen Virol. 1992 Jul;73(Pt 7):1839–1843. doi: 10.1099/0022-1317-73-7-1839. [DOI] [PubMed] [Google Scholar]
  9. Christensen J., Cotmore S. F., Tattersall P. A novel cellular site-specific DNA-binding protein cooperates with the viral NS1 polypeptide to initiate parvovirus DNA replication. J Virol. 1997 Feb;71(2):1405–1416. doi: 10.1128/jvi.71.2.1405-1416.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Corsini J., Afanasiev B., Maxwell I. H., Carlson J. O. Autonomous parvovirus and densovirus gene vectors. Adv Virus Res. 1996;47:303–351. doi: 10.1016/s0065-3527(08)60738-1. [DOI] [PubMed] [Google Scholar]
  11. Cotmore S. F., D'Abramo A. M., Jr, Carbonell L. F., Bratton J., Tattersall P. The NS2 polypeptide of parvovirus MVM is required for capsid assembly in murine cells. Virology. 1997 May 12;231(2):267–280. doi: 10.1006/viro.1997.8545. [DOI] [PubMed] [Google Scholar]
  12. Cotmore S. F., Gunther M., Tattersall P. Evidence for a ligation step in the DNA replication of the autonomous parvovirus minute virus of mice. J Virol. 1989 Feb;63(2):1002–1006. doi: 10.1128/jvi.63.2.1002-1006.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cotmore S. F., Nuesch J. P., Tattersall P. In vitro excision and replication of 5' telomeres of minute virus of mice DNA from cloned palindromic concatemer junctions. Virology. 1992 Sep;190(1):365–377. doi: 10.1016/0042-6822(92)91223-h. [DOI] [PubMed] [Google Scholar]
  14. Cotmore S. F., Tattersall P. A genome-linked copy of the NS-1 polypeptide is located on the outside of infectious parvovirus particles. J Virol. 1989 Sep;63(9):3902–3911. doi: 10.1128/jvi.63.9.3902-3911.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cotmore S. F., Tattersall P. An asymmetric nucleotide in the parvoviral 3' hairpin directs segregation of a single active origin of DNA replication. EMBO J. 1994 Sep 1;13(17):4145–4152. doi: 10.1002/j.1460-2075.1994.tb06732.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cotmore S. F., Tattersall P. In vivo resolution of circular plasmids containing concatemer junction fragments from minute virus of mice DNA and their subsequent replication as linear molecules. J Virol. 1992 Jan;66(1):420–431. doi: 10.1128/jvi.66.1.420-431.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cotmore S. F., Tattersall P. The NS-1 polypeptide of minute virus of mice is covalently attached to the 5' termini of duplex replicative-form DNA and progeny single strands. J Virol. 1988 Mar;62(3):851–860. doi: 10.1128/jvi.62.3.851-860.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Cotmore S. F., Tattersall P. The autonomously replicating parvoviruses of vertebrates. Adv Virus Res. 1987;33:91–174. doi: 10.1016/s0065-3527(08)60317-6. [DOI] [PubMed] [Google Scholar]
  19. Doerig C., Hirt B., Antonietti J. P., Beard P. Nonstructural protein of parvoviruses B19 and minute virus of mice controls transcription. J Virol. 1990 Jan;64(1):387–396. doi: 10.1128/jvi.64.1.387-396.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Doerig C., Hirt B., Beard P., Antonietti J. P. Minute virus of mice non-structural protein NS-1 is necessary and sufficient for trans-activation of the viral P39 promoter. J Gen Virol. 1988 Oct;69(Pt 10):2563–2573. doi: 10.1099/0022-1317-69-10-2563. [DOI] [PubMed] [Google Scholar]
  21. Fox E., Moen P. T., Jr, Bodnar J. W. Replication of minute virus of mice DNA in adenovirus-infected or adenovirus-transformed cells. Virology. 1990 Jun;176(2):403–412. doi: 10.1016/0042-6822(90)90010-o. [DOI] [PubMed] [Google Scholar]
  22. Giraud C., Winocour E., Berns K. I. Recombinant junctions formed by site-specific integration of adeno-associated virus into an episome. J Virol. 1995 Nov;69(11):6917–6924. doi: 10.1128/jvi.69.11.6917-6924.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Giraud C., Winocour E., Berns K. I. Site-specific integration by adeno-associated virus is directed by a cellular DNA sequence. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10039–10043. doi: 10.1073/pnas.91.21.10039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  25. Grossman Z., Berns K. I., Winocour E. Structure of simian virus 40-adeno-associated virus recombinant genomes. J Virol. 1985 Nov;56(2):457–465. doi: 10.1128/jvi.56.2.457-465.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hirt B. Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol. 1967 Jun 14;26(2):365–369. doi: 10.1016/0022-2836(67)90307-5. [DOI] [PubMed] [Google Scholar]
  27. Knoblauch M., Schröer J., Schmitz B., Doerfler W. The structure of adenovirus type 12 DNA integration sites in the hamster cell genome. J Virol. 1996 Jun;70(6):3788–3796. doi: 10.1128/jvi.70.6.3788-3796.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Koonin E. V., Ilyina T. V. Computer-assisted dissection of rolling circle DNA replication. Biosystems. 1993;30(1-3):241–268. doi: 10.1016/0303-2647(93)90074-m. [DOI] [PubMed] [Google Scholar]
  29. Kotin R. M., Berns K. I. Organization of adeno-associated virus DNA in latently infected Detroit 6 cells. Virology. 1989 Jun;170(2):460–467. doi: 10.1016/0042-6822(89)90437-6. [DOI] [PubMed] [Google Scholar]
  30. Kotin R. M., Linden R. M., Berns K. I. Characterization of a preferred site on human chromosome 19q for integration of adeno-associated virus DNA by non-homologous recombination. EMBO J. 1992 Dec;11(13):5071–5078. doi: 10.1002/j.1460-2075.1992.tb05614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kotin R. M., Menninger J. C., Ward D. C., Berns K. I. Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics. 1991 Jul;10(3):831–834. doi: 10.1016/0888-7543(91)90470-y. [DOI] [PubMed] [Google Scholar]
  32. Kotin R. M. Prospects for the use of adeno-associated virus as a vector for human gene therapy. Hum Gene Ther. 1994 Jul;5(7):793–801. doi: 10.1089/hum.1994.5.7-793. [DOI] [PubMed] [Google Scholar]
  33. Kotin R. M., Siniscalco M., Samulski R. J., Zhu X. D., Hunter L., Laughlin C. A., McLaughlin S., Muzyczka N., Rocchi M., Berns K. I. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2211–2215. doi: 10.1073/pnas.87.6.2211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ledinko N., Hopkins S., Toolan H. Relationship between potentiation of H-1 growth by human adenovirus 12 and inhibition of the 'helper' adenovirus by H-1. J Gen Virol. 1969 Jul;5(1):19–31. doi: 10.1099/0022-1317-5-1-19. [DOI] [PubMed] [Google Scholar]
  35. Li X., Rhode S. L., 3rd Nonstructural protein NS2 of parvovirus H-1 is required for efficient viral protein synthesis and virus production in rat cells in vivo and in vitro. Virology. 1991 Sep;184(1):117–130. doi: 10.1016/0042-6822(91)90828-y. [DOI] [PubMed] [Google Scholar]
  36. Linden R. M., Ward P., Giraud C., Winocour E., Berns K. I. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11288–11294. doi: 10.1073/pnas.93.21.11288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Linden R. M., Winocour E., Berns K. I. The recombination signals for adeno-associated virus site-specific integration. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7966–7972. doi: 10.1073/pnas.93.15.7966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Liu Q., Astell C. R. A murine host cell factor required for nicking of the dimer bridge of MVM recognizes two CG nucleotides displaced by 10 basepairs. Virology. 1996 Oct 1;224(1):105–113. doi: 10.1006/viro.1996.0511. [DOI] [PubMed] [Google Scholar]
  39. Liu Q., Yong C. B., Astell C. R. In vitro resolution of the dimer bridge of the minute virus of mice (MVM) genome supports the modified rolling hairpin model for MVM replication. Virology. 1994 Jun;201(2):251–262. doi: 10.1006/viro.1994.1290. [DOI] [PubMed] [Google Scholar]
  40. Margolskee R. F. Epstein-Barr virus based expression vectors. Curr Top Microbiol Immunol. 1992;158:67–95. doi: 10.1007/978-3-642-75608-5_4. [DOI] [PubMed] [Google Scholar]
  41. Merchlinsky M. J., Tattersall P. J., Leary J. J., Cotmore S. F., Gardiner E. M., Ward D. C. Construction of an infectious molecular clone of the autonomous parvovirus minute virus of mice. J Virol. 1983 Jul;47(1):227–232. doi: 10.1128/jvi.47.1.227-232.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Naeger L. K., Cater J., Pintel D. J. The small nonstructural protein (NS2) of the parvovirus minute virus of mice is required for efficient DNA replication and infectious virus production in a cell-type-specific manner. J Virol. 1990 Dec;64(12):6166–6175. doi: 10.1128/jvi.64.12.6166-6175.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Naeger L. K., Salomé N., Pintel D. J. NS2 is required for efficient translation of viral mRNA in minute virus of mice-infected murine cells. J Virol. 1993 Feb;67(2):1034–1043. doi: 10.1128/jvi.67.2.1034-1043.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nüesch J. P., Cotmore S. F., Tattersall P. Sequence motifs in the replicator protein of parvovirus MVM essential for nicking and covalent attachment to the viral origin: identification of the linking tyrosine. Virology. 1995 May 10;209(1):122–135. doi: 10.1006/viro.1995.1236. [DOI] [PubMed] [Google Scholar]
  45. Richards R. G., Armentrout R. W. Early events in parvovirus replication: lack of integration by minute virus of mice into host cell DNA. J Virol. 1979 Apr;30(1):397–399. doi: 10.1128/jvi.30.1.397-399.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rommelaere J., Vos J. M., Cornelis J. J., Ward D. C. UV-enhanced reactivation of minute-virus-of-mice: stimulation of a late step in the viral life cycle. Photochem Photobiol. 1981 Jun;33(6):845–854. doi: 10.1111/j.1751-1097.1981.tb05502.x. [DOI] [PubMed] [Google Scholar]
  47. Ron D., Tal J. Coevolution of cells and virus as a mechanism for the persistence of lymphotropic minute virus of mice in L-cells. J Virol. 1985 Aug;55(2):424–430. doi: 10.1128/jvi.55.2.424-430.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Samulski R. J., Zhu X., Xiao X., Brook J. D., Housman D. E., Epstein N., Hunter L. A. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. EMBO J. 1991 Dec;10(12):3941–3950. doi: 10.1002/j.1460-2075.1991.tb04964.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Shelling A. N., Smith M. G. Targeted integration of transfected and infected adeno-associated virus vectors containing the neomycin resistance gene. Gene Ther. 1994 May;1(3):165–169. [PubMed] [Google Scholar]
  50. Tam P., Astell C. R. Replication of minute virus of mice minigenomes: novel replication elements required for MVM DNA replication. Virology. 1993 Apr;193(2):812–824. doi: 10.1006/viro.1993.1190. [DOI] [PubMed] [Google Scholar]
  51. Tattersall P., Ward D. C. Rolling hairpin model for replication of parvovirus and linear chromosomal DNA. Nature. 1976 Sep 9;263(5573):106–109. doi: 10.1038/263106a0. [DOI] [PubMed] [Google Scholar]
  52. Urcelay E., Ward P., Wiener S. M., Safer B., Kotin R. M. Asymmetric replication in vitro from a human sequence element is dependent on adeno-associated virus Rep protein. J Virol. 1995 Apr;69(4):2038–2046. doi: 10.1128/jvi.69.4.2038-2046.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Weitzman M. D., Kyöstiö S. R., Kotin R. M., Owens R. A. Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5808–5812. doi: 10.1073/pnas.91.13.5808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yakobson B., Hrynko T. A., Peak M. J., Winocour E. Replication of adeno-associated virus in cells irradiated with UV light at 254 nm. J Virol. 1989 Mar;63(3):1023–1030. doi: 10.1128/jvi.63.3.1023-1030.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yakobson B., Koch T., Winocour E. Replication of adeno-associated virus in synchronized cells without the addition of a helper virus. J Virol. 1987 Apr;61(4):972–981. doi: 10.1128/jvi.61.4.972-981.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yalkinoglu A. O., Heilbronn R., Bürkle A., Schlehofer J. R., zur Hausen H. DNA amplification of adeno-associated virus as a response to cellular genotoxic stress. Cancer Res. 1988 Jun 1;48(11):3123–3129. [PubMed] [Google Scholar]
  57. Yates J. L., Warren N., Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. 1985 Feb 28-Mar 6Nature. 313(6005):812–815. doi: 10.1038/313812a0. [DOI] [PubMed] [Google Scholar]

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