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. 1986 Oct;60(1):251–258. doi: 10.1128/jvi.60.1.251-258.1986

Positive and negative autoregulation of the adeno-associated virus type 2 genome.

M A Labow, P L Hermonat, K I Berns
PMCID: PMC253923  PMID: 3018288

Abstract

The defective human parvovirus, adeno-associated virus (AAV), requires multiple functions provided by a coinfecting helper virus for viral replication. In addition, it has recently been shown that at least one AAV gene is also required for AAV DNA replication. In this paper, we investigate the autoregulation of the AAV genome by analyzing the expression of mutant AAV genomes upon transfection into adenovirus-infected human cells. Evidence is presented which indicates that the AAV genome regulates its own gene expression in at least two ways. First, either the AAV p5 gene or both the p5 and p19 genes appear to encode a trans activator of AAV transcription. Frameshift mutations within the p5 or p19 gene severely inhibited the synthesis and accumulation of all AAV transcripts. The defective accumulation of transcripts could be complemented in trans, in a manner independent of DNA replication, by cotransfection with a capsid deletion mutant. Second, evidence is presented which suggests that the p5 and p19 genes contain negative cis-active regulatory elements. Deletion of sequences within the p5 and p19 genes enhanced the accumulation of the p5 transcript in cis upon complementation with an AAV capsid deletion mutant, whereas certain deletions enhanced p40 RNA accumulation in the absence of trans activation by the p5 gene.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ATCHISON R. W., CASTO B. C., HAMMON W. M. ADENOVIRUS-ASSOCIATED DEFECTIVE VIRUS PARTICLES. Science. 1965 Aug 13;149(3685):754–756. doi: 10.1126/science.149.3685.754. [DOI] [PubMed] [Google Scholar]
  2. Becerra S. P., Rose J. A., Hardy M., Baroudy B. M., Anderson C. W. Direct mapping of adeno-associated virus capsid proteins B and C: a possible ACG initiation codon. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7919–7923. doi: 10.1073/pnas.82.23.7919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ben-Asher E., Aloni Y. Transcription of minute virus of mice, an autonomous parvovirus, may be regulated by attenuation. J Virol. 1984 Oct;52(1):266–276. doi: 10.1128/jvi.52.1.266-276.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berk A. J., Lee F., Harrison T., Williams J., Sharp P. A. Pre-early adenovirus 5 gene product regulates synthesis of early viral messenger RNAs. Cell. 1979 Aug;17(4):935–944. doi: 10.1016/0092-8674(79)90333-7. [DOI] [PubMed] [Google Scholar]
  5. Berns K. I., Adler S. Separation of two types of adeno-associated virus particles containing complementary polynucleotide chains. J Virol. 1972 Feb;9(2):394–396. doi: 10.1128/jvi.9.2.394-396.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berns K. I., Rose J. A. Evidence for a single-stranded adenovirus-associated virus genome: isolation and separation of complementary single strands. J Virol. 1970 Jun;5(6):693–699. doi: 10.1128/jvi.5.6.693-699.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brady J., Bolen J. B., Radonovich M., Salzman N., Khoury G. Stimulation of simian virus 40 late gene expression by simian virus 40 tumor antigen. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2040–2044. doi: 10.1073/pnas.81.7.2040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buller R. M., Janik J. E., Sebring E. D., Rose J. A. Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. J Virol. 1981 Oct;40(1):241–247. doi: 10.1128/jvi.40.1.241-247.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carter B. J., Laughlin C. A., de la Maza L. M., Myers M. Adeno-associated virus autointerference. Virology. 1979 Jan 30;92(2):449–462. doi: 10.1016/0042-6822(79)90149-1. [DOI] [PubMed] [Google Scholar]
  10. Falck-Pedersen E., Logan J., Shenk T., Darnell J. E., Jr Transcription termination within the E1A gene of adenovirus induced by insertion of the mouse beta-major globin terminator element. Cell. 1985 Apr;40(4):897–905. doi: 10.1016/0092-8674(85)90349-6. [DOI] [PubMed] [Google Scholar]
  11. Green M. R., Roeder R. G. Definition of a novel promoter for the major adenovirus-associated virus mRNA. Cell. 1980 Nov;22(1 Pt 1):231–242. doi: 10.1016/0092-8674(80)90171-3. [DOI] [PubMed] [Google Scholar]
  12. Green M. R., Roeder R. G. Transcripts of the adeno-associated virus genome: mapping of the major RNAs. J Virol. 1980 Oct;36(1):79–92. doi: 10.1128/jvi.36.1.79-92.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Green M. R., Straus S. E., Roeder R. G. Transcripts of the adenovirus-associated virus genome: multiple polyadenylated RNAs including a potential primary transcript. J Virol. 1980 Aug;35(2):560–565. doi: 10.1128/jvi.35.2.560-565.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hartzell S. W., Byrne B. J., Subramanian K. N. The simian virus 40 minimal origin and the 72-base-pair repeat are required simultaneously for efficient induction of late gene expression with large tumor antigen. Proc Natl Acad Sci U S A. 1984 Oct;81(20):6335–6339. doi: 10.1073/pnas.81.20.6335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hearing P., Shenk T. Sequence-independent autoregulation of the adenovirus type 5 E1A transcription unit. Mol Cell Biol. 1985 Nov;5(11):3214–3221. doi: 10.1128/mcb.5.11.3214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hermonat P. L., Labow M. A., Wright R., Berns K. I., Muzyczka N. Genetics of adeno-associated virus: isolation and preliminary characterization of adeno-associated virus type 2 mutants. J Virol. 1984 Aug;51(2):329–339. doi: 10.1128/jvi.51.2.329-339.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Janik J. E., Huston M. M., Rose J. A. Adeno-associated virus proteins: origin of the capsid components. J Virol. 1984 Nov;52(2):591–597. doi: 10.1128/jvi.52.2.591-597.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Janik J. E., Huston M. M., Rose J. A. Locations of adenovirus genes required for the replication of adenovirus-associated virus. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1925–1929. doi: 10.1073/pnas.78.3.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jay F. T., Laughlin C. A., Carter B. J. Eukaryotic translational control: adeno-associated virus protein synthesis is affected by a mutation in the adenovirus DNA-binding protein. Proc Natl Acad Sci U S A. 1981 May;78(5):2927–2931. doi: 10.1073/pnas.78.5.2927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Johnson F. B., Thomson T. A., Taylor P. A., Vlazny D. A. Molecular similarities among the adenovirus-associated virus polypeptides and evidence for a precursor protein. Virology. 1977 Oct 1;82(1):1–13. doi: 10.1016/0042-6822(77)90027-7. [DOI] [PubMed] [Google Scholar]
  21. Jones N., Shenk T. An adenovirus type 5 early gene function regulates expression of other early viral genes. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3665–3669. doi: 10.1073/pnas.76.8.3665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Laughlin C. A., Jones N., Carter B. J. Effect of deletions in adenovirus early region 1 genes upon replication of adeno-associated virus. J Virol. 1982 Mar;41(3):868–876. doi: 10.1128/jvi.41.3.868-876.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Laughlin C. A., Myers M. W., Risin D. L., Carter B. J. Defective-interfering particles of the human parvovirus adeno-associated virus. Virology. 1979 Apr 15;94(1):162–174. doi: 10.1016/0042-6822(79)90446-x. [DOI] [PubMed] [Google Scholar]
  24. Laughlin C. A., Tratschin J. D., Coon H., Carter B. J. Cloning of infectious adeno-associated virus genomes in bacterial plasmids. Gene. 1983 Jul;23(1):65–73. doi: 10.1016/0378-1119(83)90217-2. [DOI] [PubMed] [Google Scholar]
  25. Laughlin C. A., Westphal H., Carter B. J. Spliced adenovirus-associated virus RNA. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5567–5571. doi: 10.1073/pnas.76.11.5567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lusby E. W., Berns K. I. Mapping of the 5' termini of two adeno-associated virus 2 RNAs in the left half of the genome. J Virol. 1982 Feb;41(2):518–526. doi: 10.1128/jvi.41.2.518-526.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lusby E., Fife K. H., Berns K. I. Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J Virol. 1980 May;34(2):402–409. doi: 10.1128/jvi.34.2.402-409.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McCutchan J. H., Pagano J. S. Enchancement of the infectivity of simian virus 40 deoxyribonucleic acid with diethylaminoethyl-dextran. J Natl Cancer Inst. 1968 Aug;41(2):351–357. [PubMed] [Google Scholar]
  29. Nevins J. R. Definition and mapping of adenovirus 2 nuclear transcription. Methods Enzymol. 1980;65(1):768–785. doi: 10.1016/s0076-6879(80)65072-1. [DOI] [PubMed] [Google Scholar]
  30. O'Hare P., Hayward G. S. Three trans-acting regulatory proteins of herpes simplex virus modulate immediate-early gene expression in a pathway involving positive and negative feedback regulation. J Virol. 1985 Dec;56(3):723–733. doi: 10.1128/jvi.56.3.723-733.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rhode S. L., 3rd trans-Activation of parvovirus P38 promoter by the 76K noncapsid protein. J Virol. 1985 Sep;55(3):886–889. doi: 10.1128/jvi.55.3.886-889.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Richardson W. D., Westphal H. A cascade of adenovirus early functions is required for expression of adeno-associated virus. Cell. 1981 Nov;27(1 Pt 2):133–141. doi: 10.1016/0092-8674(81)90367-6. [DOI] [PubMed] [Google Scholar]
  33. Richardson W. D., Westphal H. Requirement for either early region 1a or early region 1b adenovirus gene products in the helper effect for adeno-associated virus. J Virol. 1984 Aug;51(2):404–410. doi: 10.1128/jvi.51.2.404-410.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rose J. A., Maizel J. V., Jr, Inman J. K., Shatkin A. J. Structural proteins of adenovirus-associated viruses. J Virol. 1971 Nov;8(5):766–770. doi: 10.1128/jvi.8.5.766-770.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Samulski R. J., Berns K. I., Tan M., Muzyczka N. Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2077–2081. doi: 10.1073/pnas.79.6.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Samulski R. J., Srivastava A., Berns K. I., Muzyczka N. Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV. Cell. 1983 May;33(1):135–143. doi: 10.1016/0092-8674(83)90342-2. [DOI] [PubMed] [Google Scholar]
  37. Senapathy P., Carter B. J. Molecular cloning of adeno-associated virus variant genomes and generation of infectious virus by recombination in mammalian cells. J Biol Chem. 1984 Apr 10;259(7):4661–4666. [PubMed] [Google Scholar]
  38. Senapathy P., Tratschin J. D., Carter B. J. Replication of adeno-associated virus DNA. Complementation of naturally occurring rep- mutants by a wild-type genome or an ori- mutant and correction of terminal palindrome deletions. J Mol Biol. 1984 Oct 15;179(1):1–20. doi: 10.1016/0022-2836(84)90303-6. [DOI] [PubMed] [Google Scholar]
  39. Smith D. H., Kegler D. M., Ziff E. B. Vector expression of adenovirus type 5 E1a proteins: evidence for E1a autoregulation. Mol Cell Biol. 1985 Oct;5(10):2684–2696. doi: 10.1128/mcb.5.10.2684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  41. Srivastava A., Lusby E. W., Berns K. I. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol. 1983 Feb;45(2):555–564. doi: 10.1128/jvi.45.2.555-564.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tratschin J. D., Miller I. L., Carter B. J. Genetic analysis of adeno-associated virus: properties of deletion mutants constructed in vitro and evidence for an adeno-associated virus replication function. J Virol. 1984 Sep;51(3):611–619. doi: 10.1128/jvi.51.3.611-619.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tratschin J. D., West M. H., Sandbank T., Carter B. J. A human parvovirus, adeno-associated virus, as a eucaryotic vector: transient expression and encapsidation of the procaryotic gene for chloramphenicol acetyltransferase. Mol Cell Biol. 1984 Oct;4(10):2072–2081. doi: 10.1128/mcb.4.10.2072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Velcich A., Ziff E. Adenovirus E1a proteins repress transcription from the SV40 early promoter. Cell. 1985 Mar;40(3):705–716. doi: 10.1016/0092-8674(85)90219-3. [DOI] [PubMed] [Google Scholar]
  45. Wigler M., Pellicer A., Silverstein S., Axel R., Urlaub G., Chasin L. DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1373–1376. doi: 10.1073/pnas.76.3.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]

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