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Molecular Biology

, Volume 38, Issue 5, pp 718–727 | Cite as

Interactions of HIV-1 DNA Heterocyclic Bases with Viral Integrase

  • J. J. Agapkina
  • V. N. Tashlitskii
  • E. Deprez
  • J.-C. Brochon
  • A. V. Shugalii
  • J.-F. Mouscadet
  • M. B. Gottikh
Article

Abstract

Integrase (IN) is responsible for one of the key stages in the replication cycle of human immunodeficiency virus type 1, namely, integration of a DNA copy of the viral RNA into the infected cell genome. IN recognizes the nucleotide sequences located at the ends of the U3 and U5 regions of long terminal repeats (LTRs) of the viral DNA and sequentially catalyzes the 3′-end processing and strand transfer reactions. Analogs of U5 regions containing non-nucleoside insertions have been used to study the interaction between IN and viral DNA. Substrate modification has been demonstrated to have almost no effect on the rate of DNA binding by IN. However, the removal of heterocyclic bases from positions 5 and 6 of the substrate molecule and from position 3 of the processed strand almost completely inhibits IN enzymatic activity, which indicates the importance of these bases for the formation of an active enzyme–substrate complex. By contrast, modification of the third base of the nonprocessed strand stimulates 3′-processing. Since the base removal disturbs the complementary and stacking interactions in DNA, these results indicate that double-helix destabilization near the cleaved bond promotes 3′-end processing.

human immunodeficiency virus type 1 integrase DNA modification the fluorescence polarization method 3′-end processing 

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REFERENCES

  1. 1.
    Brown P.O. 1990. Integration of retroviral DNA. Curr. Top. Microbiol. Immunol. 157, 19–48.PubMedGoogle Scholar
  2. 2.
    Ferguson M.R., Rojo D.R., von Lindern J.J., O'Brien W.A. 2002. HIV-1 replication cycle. Clin. Lab. Med. 22, 611–635.PubMedGoogle Scholar
  3. 3.
    Brin E., Yi J., Skalka A., Leis J. 2000. Modeling the late steps in HIV-1 retroviral integrase-catalyzed DNA inte-gration. J. Biol. Chem. 275, 39287–39295.PubMedGoogle Scholar
  4. 4.
    Engelman A., Bushman F.D., Craigie R. 1993. Identifi-cation of discrete functional domains of HIV-1 integrase and their organization within an active multimeric com-plex. EMBO J. 12, 3269–3275.PubMedGoogle Scholar
  5. 5.
    Vink C., Groeneger A.A., Plasterk R. 1993. Identifica-tion of the catalytic and DNA-binding region of the human immunodeficiency virus type 1 integrase protein. Nucleic Acids Res. 21, 1419–1425.Google Scholar
  6. 6.
    Esposito D., Craigie R. 1999. HIV integrase structure and function. Adv. Virus Res. 52, 319–333.Google Scholar
  7. 7.
    Cherepanov P., Maertens G., Proost P., Devreese B., van Beeumen J., Engelborgh Y., De Clercq E., Debyser Z. 2003. HIV-1 integrase forms stable tetramers and associ-ates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372–381.PubMedGoogle Scholar
  8. 8.
    Deprez E., Tauc P., Leh H., Mouscadet J.-F., Auclair C., Brochon J.-C. 2000. Oligomeric state of the HIV-1 inte-grase as measured by time-resolved fluorescence anisot-ropy. Biochemistry. 39, 9275–9284.Google Scholar
  9. 9.
    Chen J.C.-H., Krucinski J., Miercke L.J.W., Finer-Moore J.S., Tang A.H., Leavitt A.D., Stroud R.M. 2000. Crystal structure of the HIV-1 integrase catalytic and C-terminal domains: A model for viral DNA binding. Bio-chemistry. 97, 8233–8238.Google Scholar
  10. 10.
    Gao K., Bulter S.L., Bushman F. 2001. Human immun-odeficiency virus type 1 integrase: Arrangement of pro-tein domains in active cDNA complexes. EMBO J. 20, 3565–3576.PubMedGoogle Scholar
  11. 11.
    Podtelezhnikov A.A., Gao K., Bushman F.D., McCam-mon J.A. 2003. Modeling HIV-1 integrase complexes based on their hydrodynamic properties. Biopolymers. 68, 110–120.PubMedGoogle Scholar
  12. 12.
    Perryman A.L., McCammon J.A. 2002. AutoDocking dinucleotides to the HIV-1 integrase core domain: Exploring possible binding sites for viral and genomic DNA. J. Med. Chem. 45, 5624–5627.PubMedGoogle Scholar
  13. 13.
    Heuer T.S., Brown P.O. 1997. Mapping features of HIV-1 integrase near selected sites on viral and target DNA molecules in an active enzyme-DNA complex by photo-cross-linking. Biochemistry. 36, 10655–10665.Google Scholar
  14. 14.
    Bugreev D.V., Baranova S., Zakharova O.D., Parissi V., Desjobert C., Sottofattori E., Balbi A., Litvak S., Tar-rago-Litvak L., Nevinsky G.A. 2003. Dynamic, thermo-dynamic, and kinetic basis for recognition and transfor-mation of DNA by human immunodeficiency virus type 1 integrase. Biochemistry. 42, 9235–9247.PubMedGoogle Scholar
  15. 15.
    LaFemina R.L., Callahan P.L., Cordingley M.G. 1991. Substrate specificity of recombinant human immunode-ficiency virus integrase protein. J. Virol. 65, 5624–5630.PubMedGoogle Scholar
  16. 16.
    Sherman P.A., Dikson M.L., Fyfe J.A. 1992. Human immunodeficiency virus type 1 integrase protein: DNA sequence requirements for cleaving and joining reaction. J. Virol. 66, 3593–3601.PubMedGoogle Scholar
  17. 17.
    Mazumder A., Pommier Y. 1995.Processing of deox-yuridine mismatches and abasic sites by human immun-odeficiency virus type-1 integrase. Nucleic Acids Res. 23, 2865–2871.PubMedGoogle Scholar
  18. 18.
    Van den Ent F.M., Vink C., Plasterk R.H. 1994. DNA substrate requirements for different activities of the human immunodeficiency virus type 1 integrase protein. J. Virol. 68, 7825–7832.PubMedGoogle Scholar
  19. 19.
    Esposito D., Craigie R. 1998. Sequence specificity of viral end DNA binding by HIV-1 integrase reveals criti-cal regions for protein DNA interactions. EMBO J. 17, 5832–5843.PubMedGoogle Scholar
  20. 20.
    Wang T., Balakrishnan M., Jonsson C.B. 1999. Major and minor groove contacts in retroviral integrase-LTR interactions. Biochemistry. 38, 3624–3632.Google Scholar
  21. 21.
    Engelman A., Craigie R. 1995. Efficient magnesium-dependent human immunodeficiency virus type 1 inte-grase activity. J. Virol. 69, 5908–5911.PubMedGoogle Scholar
  22. 22.
    Leh H., Brodin P., Bischerour J., Deprez E., Tauc P., Brochon J.C., LeCam E., Coulaud D., Auclair C., Mouscadet J.F. 2000. Determinants of Mg2+-depen-dent activities of recombinant human immunodefi-ciency virus type 1 integrase. Biochemistry. 39, 928–9294.Google Scholar
  23. 23.
    Helin V., Gottikh M.B., Mishal Z., Subra F., Malvy C., Lavignon M. 1999. Cell cycle-dependent distribution and specific inhibitory effect of vectorized antisense oli-gonucleotides in cell culture. Biochem. Pharmacol. 58, 95–107.Google Scholar
  24. 24.
    Gelfand C.A., Plum G.E., Grollman A.P., Johnson F., Breslauer K.J. 1998. Thermodynamic consequences of an abasic lesion in duplex DNA are strongly dependent on base sequence. Biochemistry. 37, 7321–7327.Google Scholar
  25. 25.
    Dyda F., Hickman B., Jenkins T.M., Engelman A., Craigie R., Davies D.R. 1994. Crystal structure of the catalytic domain of HIV-1 integrase: Similarity to other polynucleotidyl transferases. Science. 266, 1981–1986.PubMedGoogle Scholar
  26. 26.
    Rice P.A., Baker T.A. 2001. Comparative architecture of transposase and integrase complexes. Nature Struct. Biol. 8, 302–307.Google Scholar
  27. 27.
    Haren L., Ton-Hoang B., Chandler M. 1999. Integrating DNA: Transposases and retroviral integrases. Annu. Rev. Microbiol. 53, 245–281.PubMedGoogle Scholar
  28. 28.
    Hansen M.S., Bushman F.D. 1997. Human immunodefi-ciency virus type 2 preintegration complexes: Activities in vitro and response to inhibitors. J. Virol. 71, 335--3356.Google Scholar
  29. 29.
    Burke C.J., Sanyal G., Bruner M.W., Ryan J.A., LaFemina R.L., Robbins H.L., Zeft A.S., Mid-daugh C.R., Cordingley M.G. 1992. Structural implica-tions of spectroscopic characterization of a putative zinc finger peptide from HIV-1 integrase. J. Biol. Chem. 267, 9639–9644PubMedGoogle Scholar
  30. 30.
    Bushman F.D., Engelman A., Palmer L., Wingfield P., Craigie R. 1993. Domains of the integrase protein of human immunodeficiency virus type 1 responsible for polynucleotidyl transfer and zinc binding. Proc. Natl. Acad. Sci. USA. 90, 3428–3432.PubMedGoogle Scholar
  31. 31.
    Zheng R., Jenkins T.M., Craigie R. 1996. Zinc folds the N-terminal of HIV-1 integrase, promotes multimeriza-tion, and enhances catalytic activity. Proc. Natl. Acad. Sci. USA. 93, 13659–13664.PubMedGoogle Scholar
  32. 32.
    Dickerson R.E. 1998. DNA bending: The prevalence of kinkiness and the virtues of normality. Nucleic Acids Res. 26, 1906–1926.PubMedGoogle Scholar
  33. 33.
    Packer M.J., Dauncey M.P., Hunter C.A. 2000. Sequence-dependent DNA structure: Dinucleotide con-formational maps. J. Mol. Biol. 295, 71–83.PubMedGoogle Scholar
  34. 34.
    Bertrand H., Ha-Duong T., Fermandjian S., Hartmann B. 1998. Flexibility of the B-DNA backbone: Effects of local and neighbouring sequences on pyrimidine-purine steps. Nucleic Acids Res. 26, 1261–1267.PubMedGoogle Scholar
  35. 35.
    Dickerson R.E., Chiu T.K. 1997. Helix bending as a fac-tor in protein/DNA recognition. Biopolymers. 44, 36--403.Google Scholar
  36. 36.
    Jones S., van Heyningen P., Berman H.M., Thornton J.M. 1999. Protein-DNA interactions: A struc-tural analysis. J. Mol. Biol. 287, 877–896.PubMedGoogle Scholar
  37. 37.
    Marathias V.M., Jerkovic B., Bolton P.H. 1999. Damage increases the flexibility of duplex DNA. Nucleic Acids Res. 27, 1854–1858.PubMedGoogle Scholar

Copyright information

© MAIK “Nauka/Interperiodica” 2004

Authors and Affiliations

  • J. J. Agapkina
    • 1
  • V. N. Tashlitskii
    • 1
  • E. Deprez
    • 2
  • J.-C. Brochon
    • 2
  • A. V. Shugalii
    • 1
  • J.-F. Mouscadet
    • 2
  • M. B. Gottikh
    • 3
  1. 1.Institute of the Problems of Chemical PhysicsRussian Academy of SciencesMoscowRussia
  2. 2.LBPA, UMR 8113 CNRS, IFR121, École Normale Supérieure de CachanCachan CedexFrance
  3. 3.Faculty of Chemistry and Belozersky Institute of Physico-Chemical BiologyMoscow State UniversityMoscowRussia

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