Abstract
The Rep proteins of adeno-associated virus type 2 (AAV) are known to bind to Rep recognition sequences (RRSs) in the AAV inverted terminal repeats (ITRs), the AAV p5 promoter, and the preferred AAV integration site in human chromosome 19, called AAVS1. Integration of the AAV genome into AAVS1 appears to be mediated by an interaction between the Rep proteins of AAV and Rep binding sites within the viral genome and the integration locus. In an attempt to identify potential alternate integration sites, we looked for recognition sites for AAV Rep proteins in the human genome by performing a BLASTN computerized homology search. We used the 16-mer core sequences of the RRSs in the AAV ITRs and AAVS1 separately as query sequences and identified 18 new RRSs in or flanking the genes coding for the following: tyrosine kinase activator protein 1 (TKA-1); colony stimulating factor-1; insulin-like growth factor binding protein 2 (IGFBP-2); histone H2B.1; basement membrane heparan sulfate proteoglycan, also known as perlecan; the AF-9 gene product, which is involved in the chromosomal translocation t (9:11)(p22:q23); the betaB subunit of the hormone known as inhibin; interleukin-2 enhancer binding factor; an endoplasmic reticulum-Golgi intermediate compartment resident protein called p63; a global transcription activator (hSNF2L); the beta-actin repair domain; a retinoic acid-inducible factor, also known as midkine; a breast tumor autoantigen; a growth-arrest- and DNA-damage-inducible protein called gadd45; the cyclin-dependent kinase inhibitor called KIP2, which inhibits several G1 cyclin-cyclin-dependent kinase complexes; and the hereditary breast and ovarian cancer gene (BRCA1). RRSs were also identified in a newly discovered open reading frame on chromosome 10 and in the ERCC1 locus on human chromosome 19. The ability of a maltose binding protein-Rep68 fusion protein to bind to these sequences was confirmed by electrophoretic mobility shift assays. These sites may serve as alternate integration sites for AAV or play a role in Rep-mediated effects on human cells.
Full Text
The Full Text of this article is available as a PDF (1.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
- Antoni B. A., Rabson A. B., Miller I. L., Trempe J. P., Chejanovsky N., Carter B. J. Adeno-associated virus Rep protein inhibits human immunodeficiency virus type 1 production in human cells. J Virol. 1991 Jan;65(1):396–404. doi: 10.1128/jvi.65.1.396-404.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chiorini J. A., Weitzman M. D., Owens R. A., Urcelay E., Safer B., Kotin R. M. Biologically active Rep proteins of adeno-associated virus type 2 produced as fusion proteins in Escherichia coli. J Virol. 1994 Feb;68(2):797–804. doi: 10.1128/jvi.68.2.797-804.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chiorini J. A., Wiener S. M., Owens R. A., Kyöstió S. R., Kotin R. M., Safer B. Sequence requirements for stable binding and function of Rep68 on the adeno-associated virus type 2 inverted terminal repeats. J Virol. 1994 Nov;68(11):7448–7457. doi: 10.1128/jvi.68.11.7448-7457.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chiorini J. A., Yang L., Safer B., Kotin R. M. Determination of adeno-associated virus Rep68 and Rep78 binding sites by random sequence oligonucleotide selection. J Virol. 1995 Nov;69(11):7334–7338. doi: 10.1128/jvi.69.11.7334-7338.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen I. R., Grässel S., Murdoch A. D., Iozzo R. V. Structural characterization of the complete human perlecan gene and its promoter. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10404–10408. doi: 10.1073/pnas.90.21.10404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collart D., Ramsey-Ewing A., Bortell R., Lian J., Stein J., Stein G. Isolation and characterization of a cDNA from a human histone H2B gene which is reciprocally expressed in relation to replication-dependent H2B histone genes during HL60 cell differentiation. Biochemistry. 1991 Feb 12;30(6):1610–1617. doi: 10.1021/bi00220a024. [DOI] [PubMed] [Google Scholar]
- Collart D., Romain P. L., Huebner K., Pockwinse S., Pilapil S., Cannizzaro L. A., Lian J. B., Croce C. M., Stein J. L., Stein G. S. A human histone H2B.1 variant gene, located on chromosome 1, utilizes alternative 3' end processing. J Cell Biochem. 1992 Dec;50(4):374–385. doi: 10.1002/jcb.240500406. [DOI] [PubMed] [Google Scholar]
- Ehrenborg E., Vilhelmsdotter S., Bajalica S., Larsson C., Stern I., Koch J., Brøndum-Nielsen K., Luthman H. Structure and localization of the human insulin-like growth factor-binding protein 2 gene. Biochem Biophys Res Commun. 1991 May 15;176(3):1250–1255. doi: 10.1016/0006-291x(91)90420-c. [DOI] [PubMed] [Google Scholar]
- Fairhurst J. L., Kretschmer P. J., Kovacs E., Böhlen P., Kovesdi I. Structure of the gene coding for the human retinoic acid-inducible factor, MK. DNA Cell Biol. 1993 Mar;12(2):139–147. doi: 10.1089/dna.1993.12.139. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Hermonat P. L. Down-regulation of the human c-fos and c-myc proto-oncogene promoters by adeno-associated virus Rep78. Cancer Lett. 1994 Jun 30;81(2):129–136. doi: 10.1016/0304-3835(94)90193-7. [DOI] [PubMed] [Google Scholar]
- Hermonat P. L. Inhibition of H-ras expression by the adeno-associated virus Rep78 transformation suppressor gene product. Cancer Res. 1991 Jul 1;51(13):3373–3377. [PubMed] [Google Scholar]
- Hermonat P. L. The adeno-associated virus Rep78 gene inhibits cellular transformation induced by bovine papillomavirus. Virology. 1989 Sep;172(1):253–261. doi: 10.1016/0042-6822(89)90127-x. [DOI] [PubMed] [Google Scholar]
- Hollander M. C., Alamo I., Jackman J., Wang M. G., McBride O. W., Fornace A. J., Jr Analysis of the mammalian gadd45 gene and its response to DNA damage. J Biol Chem. 1993 Nov 15;268(32):24385–24393. [PubMed] [Google Scholar]
- Im D. S., Muzyczka N. Factors that bind to adeno-associated virus terminal repeats. J Virol. 1989 Jul;63(7):3095–3104. doi: 10.1128/jvi.63.7.3095-3104.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Im D. S., Muzyczka N. The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity. Cell. 1990 May 4;61(3):447–457. doi: 10.1016/0092-8674(90)90526-k. [DOI] [PubMed] [Google Scholar]
- Ivanchenko M., Zlatanova J., Varga-Weisz P., Hassan A., van Holde K. Linker histones affect patterns of digestion of supercoiled plasmids by single-strand-specific nucleases. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6970–6974. doi: 10.1073/pnas.93.14.6970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kallunki P., Tryggvason K. Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Cell Biol. 1992 Jan;116(2):559–571. doi: 10.1083/jcb.116.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawasaki E. S., Ladner M. B., Wang A. M., Van Arsdell J., Warren M. K., Coyne M. Y., Schweickart V. L., Lee M. T., Wilson K. J., Boosman A. Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1). Science. 1985 Oct 18;230(4723):291–296. doi: 10.1126/science.2996129. [DOI] [PubMed] [Google Scholar]
- Khleif S. N., Myers T., Carter B. J., Trempe J. P. Inhibition of cellular transformation by the adeno-associated virus rep gene. Virology. 1991 Apr;181(2):738–741. doi: 10.1016/0042-6822(91)90909-u. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- Kyöstiö S. R., Wonderling R. S., Owens R. A. Negative regulation of the adeno-associated virus (AAV) P5 promoter involves both the P5 rep binding site and the consensus ATP-binding motif of the AAV Rep68 protein. J Virol. 1995 Nov;69(11):6787–6796. doi: 10.1128/jvi.69.11.6787-6796.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ladner M. B., Martin G. A., Noble J. A., Nikoloff D. M., Tal R., Kawasaki E. S., White T. J. Human CSF-1: gene structure and alternative splicing of mRNA precursors. EMBO J. 1987 Sep;6(9):2693–2698. doi: 10.1002/j.1460-2075.1987.tb02561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li C., Lai C. F., Sigman D. S., Gaynor R. B. Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7739–7743. doi: 10.1073/pnas.88.17.7739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li C., Lusis A. J., Sparkes R., Nirula A., Gaynor R. Characterization and chromosomal mapping of the gene encoding the cellular DNA binding protein ILF. Genomics. 1992 Jul;13(3):665–671. doi: 10.1016/0888-7543(92)90139-j. [DOI] [PubMed] [Google Scholar]
- 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]
- Martin-Gallardo A., McCombie W. R., Gocayne J. D., FitzGerald M. G., Wallace S., Lee B. M., Lamerdin J., Trapp S., Kelley J. M., Liu L. I. Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3. Nat Genet. 1992 Apr;1(1):34–39. doi: 10.1038/ng0492-34. [DOI] [PubMed] [Google Scholar]
- Mason A. J., Berkemeier L. M., Schmelzer C. H., Schwall R. H. Activin B: precursor sequences, genomic structure and in vitro activities. Mol Endocrinol. 1989 Sep;3(9):1352–1358. doi: 10.1210/mend-3-9-1352. [DOI] [PubMed] [Google Scholar]
- Matsuoka S., Edwards M. C., Bai C., Parker S., Zhang P., Baldini A., Harper J. W., Elledge S. J. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 1995 Mar 15;9(6):650–662. doi: 10.1101/gad.9.6.650. [DOI] [PubMed] [Google Scholar]
- Nakamura T., Alder H., Gu Y., Prasad R., Canaani O., Kamada N., Gale R. P., Lange B., Crist W. M., Nowell P. C. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4631–4635. doi: 10.1073/pnas.90.10.4631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N., Kawarabayasi Y., Ishikawa K., Tabata S. Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1994;1(5):223–229. doi: 10.1093/dnares/1.5.223. [DOI] [PubMed] [Google Scholar]
- Okabe I., Bailey L. C., Attree O., Srinivasan S., Perkel J. M., Laurent B. C., Carlson M., Nelson D. L., Nussbaum R. L. Cloning of human and bovine homologs of SNF2/SWI2: a global activator of transcription in yeast S. cerevisiae. Nucleic Acids Res. 1992 Sep 11;20(17):4649–4655. doi: 10.1093/nar/20.17.4649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Owens R. A., Trempe J. P., Chejanovsky N., Carter B. J. Adeno-associated virus rep proteins produced in insect and mammalian expression systems: wild-type and dominant-negative mutant proteins bind to the viral replication origin. Virology. 1991 Sep;184(1):14–22. doi: 10.1016/0042-6822(91)90817-u. [DOI] [PubMed] [Google Scholar]
- Papathanasiou M. A., Kerr N. C., Robbins J. H., McBride O. W., Alamo I., Jr, Barrett S. F., Hickson I. D., Fornace A. J., Jr Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C. Mol Cell Biol. 1991 Feb;11(2):1009–1016. doi: 10.1128/mcb.11.2.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryan J. H., Zolotukhin S., Muzyczka N. Sequence requirements for binding of Rep68 to the adeno-associated virus terminal repeats. J Virol. 1996 Mar;70(3):1542–1553. doi: 10.1128/jvi.70.3.1542-1553.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Schlehofer J. R., Ehrbar M., zur Hausen H. Vaccinia virus, herpes simplex virus, and carcinogens induce DNA amplification in a human cell line and support replication of a helpervirus dependent parvovirus. Virology. 1986 Jul 15;152(1):110–117. doi: 10.1016/0042-6822(86)90376-4. [DOI] [PubMed] [Google Scholar]
- Schweizer A., Rohrer J., Jenö P., DeMaio A., Buchman T. G., Hauri H. P. A reversibly palmitoylated resident protein (p63) of an ER-Golgi intermediate compartment is related to a circulatory shock resuscitation protein. J Cell Sci. 1993 Mar;104(Pt 3):685–694. doi: 10.1242/jcs.104.3.685. [DOI] [PubMed] [Google Scholar]
- 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]
- Sun X. L., Murphy B. R., Li Q. J., Gullapalli S., Mackins J., Jayaram H. N., Srivastava A., Antony A. C. Transduction of folate receptor cDNA into cervical carcinoma cells using recombinant adeno-associated virions delays cell proliferation in vitro and in vivo. J Clin Invest. 1995 Sep;96(3):1535–1547. doi: 10.1172/JCI118192. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tokino T., Urano T., Furuhata T., Matsushima M., Miyatsu T., Sasaki S., Nakamura Y. Characterization of the human p57KIP2 gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis. Hum Genet. 1996 May;97(5):625–631. doi: 10.1007/BF02281873. [DOI] [PubMed] [Google Scholar]
- Uehara K., Matsubara S., Kadomatsu K., Tsutsui J., Muramatsu T. Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor. J Biochem. 1992 May;111(5):563–567. doi: 10.1093/oxfordjournals.jbchem.a123797. [DOI] [PubMed] [Google Scholar]
- 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]
- Walz C., Schlehofer J. R. Modification of some biological properties of HeLa cells containing adeno-associated virus DNA integrated into chromosome 17. J Virol. 1992 May;66(5):2990–3002. doi: 10.1128/jvi.66.5.2990-3002.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Wonderling R. S., Kyöstiö S. R., Owens R. A. A maltose-binding protein/adeno-associated virus Rep68 fusion protein has DNA-RNA helicase and ATPase activities. J Virol. 1995 Jun;69(6):3542–3548. doi: 10.1128/jvi.69.6.3542-3548.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wonderling R. S., Owens R. A. The Rep68 protein of adeno-associated virus type 2 stimulates expression of the platelet-derived growth factor B c-sis proto-oncogene. J Virol. 1996 Jul;70(7):4783–4786. doi: 10.1128/jvi.70.7.4783-4786.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang Q., Chen F., Trempe J. P. Characterization of cell lines that inducibly express the adeno-associated virus Rep proteins. J Virol. 1994 Aug;68(8):4847–4856. doi: 10.1128/jvi.68.8.4847-4856.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]