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Symmetrical base preferences surrounding HIV-1, avian sarcoma/leukosis virus, and murine leukemia virus integration sites
Open accessAbstract
To investigate retroviral integration targeting on a nucleotide scale, we examined the base frequencies directly surrounding cloned in vivo HIV-1, murine leukemia virus, and avian sarcoma/leukosis virus integrations. Base preferences of up to 2-fold the expected frequencies were found for three viruses, representing P values down to <10 -100 and defining what appear to be preferred integration sequences. Offset symmetry reflecting the topology of the integration reaction was found for HIV-1 and avian sarcoma/leukosis virus but not murine leukemia virus, suggesting fundamental differences in the way different retroviral integration complexes interact with host-cell DNA.
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“Briefly, there seems to be a consensus, especially noticed in the retroviral integration site alignments, that a weak pal motif is often present in the target DNA sequences that are recognized by IN (Stevens and Griffith 1996, Holman and Coffin 2005, Wu et al. 2005, Miklík et al. 2023).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Holman and Coffin 2005
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Cited by
Sorted by citations
Wang, G. P., Ciuffi, A., Leipzig, J., Berry, C. C., & Bushman, F. D. (2007) · Genome Research · doi:10.1101/gr.6286907 · Cited by 457
“A weakly conserved inverted repeat sequence from base position 3 to 7 was observed, matching that reported previously (Stevens and Griffith 1996; Carteau et al. 1998; Holman and Coffin 2005; Wu et al. 2005; Berry et al. 2006).”
Shun, M.-C., Raghavendra, N. K., Vandegraaff, N., Daigle, J. E., Hughes, S., Kellam, P., Cherepanov, P., & Engelman, A. (2007) · Genes & Development · doi:10.1101/gad.1565107 · Cited by 467
“Taken together, we conclude that IN is structurally and functionally intact in the absence of cellular LEDGF/p75 and, by extension, that the propensity for different retroviruses to integrate at weakly preferred target DNA sequences (Holman and Coffin 2005) is mechanistically separable from the targeting machineries t…”
BackgroundMethodInfluentialHIV-1 Integration Landscape during Latent and Active Infection
Cohn, L. B., da Silva, I. T., Oliveira, T. Y., Rosales, R., Parrish, E. H., Learn, G. H., Hahn, B. H., Czartoski, J., McElrath, M. J., Lehmann, C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.020 · Cited by 460
“TG-(N)5-7-CA sequence has been associated with sites of HIV-1 integration, but an integration consensus has not been defined (Brady et al., 2009; Holman and Coffin, 2005; Lewinski et al., 2006; Serrao et al., 2014; Wang et al., 2007; Wu et al., 2005).”
BackgroundGenome-wide analysis of retroviral DNA integration
Bushman, F. D., Lewinski, M. K., Ciuffi, A., Barr, S. D., Leipzig, J. N., Hannenhalli, S. S., & Hoffmann, C. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1263 · Cited by 437
“and, in vivo , the influence of the primary DNA sequence of the target site on integration is weak, thus target-site selection is primarily not sequence-specifi”
BackgroundRetroviral DNA integration: viral and cellular determinants of target-site selection
Lewinski, M. K., Yamashita, M., Emerman, M., Ciuffi, A., Marshall, H., Crawford, G., Collins, F., Shinn, P., Leipzig, J., Hannenhalli, S., et al. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020060 · Cited by 364
“Previous studies showed that retroviruses have weak preferences for specific primary DNA sequences at integration sites and, when large numbers of sites are analyzed, these biases become statistically very significant [4–7].”
Craigie, R., & Bushman, F. D. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006890 · Cited by 327
The mechanism of retroviral integration from X-ray structures of its key intermediates
Maertens, G. N., Hare, S., & Cherepanov, P. (2010) · Nature · doi:10.1038/nature09517 · Cited by 296
Integration site selection by retroviruses and transposable elements in eukaryotes
Sultana, T., Zamborlini, A., Cristofari, G., & Lesage, P. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2017.7 · Cited by 275
Role of PSIP1/LEDGF/p75 in Lentiviral Infectivity and Integration Targeting
Marshall, H. M., Ronen, K., Berry, C., Llano, M., Sutherland, H., Saenz, D., Bickmore, W., Poeschla, E., & Bushman, F. D. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001340 · Cited by 241
Integrase and integration: biochemical activities of HIV-1 integrase
Delelis, O., Carayon, K., Saı̈b, A., Deprez, E., & Mouscadet, J. F. (2008) · Retrovirology · doi:10.1186/1742-4690-5-114 · Cited by 261
“Recently, mapping of extensive integration sites, notably for HIV-1, put in light the existence of a weak palindromic consensus [44-46].”
BackgroundLesbats, P., Engelman, A., & Cherepanov, P. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00125 · Cited by 250
The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication
Engelman, A., & Cherepanov, P. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000046 · Cited by 231
HIV Integration Targeting: A Pathway Involving Transportin-3 and the Nuclear Pore Protein RanBP2
Ocwieja, K. E., Brady, T. L., Ronen, K., Huegel, A., Roth, S. L., Schaller, T., James, L. C., Towers, G. J., Young, J. A. T., Chanda, S. K., et al. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1001313 · Cited by 212
Selection of Target Sites for Mobile DNA Integration in the Human Genome
Berry, C., Hannenhalli, S., Leipzig, J., & Bushman, F. (2006) · PLoS Comput. Biol. · doi:10.1371/journal.pcbi.0020157 · Cited by 210
“Weaker but still quite significant effects are seen for the retroviruses [31–34].”
BackgroundDerse, D., Crise, B. J., Li, Y., Princler, G. L., Lum, N., Stewart, C., McGrath, C. F., Hughes, S. H., Munroe, D. J., & Wu, X. (2007) · Journal of Virology · doi:10.1128/jvi.02752-06 · Cited by 180
“Previous analysis of local DNA sequences around the target sites has shown that a palindromic consensus sequence is a common feature for the proviruses of HIV, SIV, MLV, and ASLV (26, 58).”
BackgroundCherepanov, P. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkl885 · Cited by 173
“Weak consensus integration site sequences have been reported for HIV-1, avian sarcoma leukosis virus (ASLV) and murine leukemia virus (MLV) (6).”
BackgroundResultInfluentialNuclear landscape of HIV-1 infection and integration
Lušić, M., & Siliciano, R. F. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.162 · Cited by 168
Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro
Christensen, D. E., Ganser-Pornillos, B. K., Johnson, J. S., Pornillos, O., & Sundquist, W. I. (2020) · Science · doi:10.1126/science.abc8420 · Cited by 150
Matreyek, K. A., & Engelman, A. (2013) · Viruses · doi:10.3390/v5102483 · Cited by 160
“IN favors certain nucleotide patterns at the site of integration [176,177].”
BackgroundGupta, S. S., Maetzig, T., Maertens, G. N., Sharif, A., Rothe, M., Weidner-Glunde, M., Galla, M., Schambach, A., Cherepanov, P., & Schulz, T. F. (2013) · Journal of Virology · doi:10.1128/jvi.01942-13 · Cited by 139
“To clone FLAG-tagged deletion constructs for MLV IN, IN fragments were PCR amplified from pQMLV-IN-FLAG plasmid using the following primer pairs: IN(110-409) ( NTD), SG1 and PC595; IN(160-409) ( CCD), SG2 and PC595; IN(1-278) ( CTD), PC594 and SG3; IN(160359) ( CCD CTD), SG2 and SG4.”
MethodHIV integration site distributions in resting and activated CD4 + T cells infected in culture
Brady, T., Agosto, L. M., Malani, N., Berry, C. C., O’Doherty, U., & Bushman, F. D. (2009) · AIDS · doi:10.1097/qad.0b013e32832caf28 · Cited by 154
“Comparison of primary sequences at integration sites HIV is known to favor integration at the weakly conserved palindromic sequence 50-GT(A/T)AC-30 at the point of integration [22,32–35].”
Relationship between the Oligomeric Status of HIV-1 Integrase on DNA and Enzymatic Activity
Guiot, E., Carayon, K., Delelis, O., Simon, F., Tauc, P., Zubin, E. M., Gottikh, M., Mouscadet, J. F., Brochon, J., & Deprez, E. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602198200 · Cited by 145
Wang, G. P., Levine, B. L., Binder, G. K., Berry, C. C., Malani, N., McGarrity, G., Tebas, P., June, C. H., & Bushman, F. D. (2009) · Molecular Therapy · doi:10.1038/mt.2009.16 · Cited by 147
Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration
Ferris, A. L., Wu, X., Hughes, C. M., Stewart, C., Smith, S. J., Milne, T. A., Wang, G. G., Shun, M.-C., Allis, C. D., Engelman, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914142107 · Cited by 146
“The palindrome preferences of the various retroviruses seem to reflect preferences of their respective INs (6, 28, 29).”
BackgroundThe LORE 1 insertion mutant resource
Małolepszy, A., Mun, T., Sandal, N., Gupta, V., Dubin, M., Urbański, D. F., Shah, N., Bachmann, A., Fukai, E., Hirakawa, H., et al. (2016) · The Plant Journal · doi:10.1111/tpj.13243 · Cited by 133
HIV-1 Pre-Integration Complexes Selectively Target Decondensed Chromatin in the Nuclear Periphery
Albanese, A., Arosio, D., Terreni, M., & Cereseto, A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002413 · Cited by 140
Retroviral DNA Integration—Mechanism and Consequences
Lewinski, M. K., & Bushman, F. D. (2005) · Advances in genetics · doi:10.1016/s0065-2660(05)55005-3 · Cited by 140
“target DNA (Carteau, et al., 1998; Holman and Coffin, 2005; Stevens and Griffith, 1996; Wu, et al., 2005), but integration in vivo shows pronounced favored and”
BackgroundMolecular mechanisms of retroviral integration site selection
Kvaratskhelia, M., Sharma, A., Larue, R. C., Serrao, E., & Engelman, A. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku769 · Cited by 150
Schrijvers, R., Rijck, J. D., Demeulemeester, J., Adachi, N., Vets, S., Ronen, K., Christ, F., Bushman, F. D., Debyser, Z., & Gijsbers, R. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002558 · Cited by 139
Integrase, LEDGF/p75 and HIV replication
Poeschla, E. M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7540-5 · Cited by 140
Koh, Y., Wu, X., Ferris, A. L., Matreyek, K. A., Smith, S. J., Lee, K., KewalRamani, V. N., Hughes, S. H., & Engelman, A. (2013) · Journal of Virology · doi:10.1128/jvi.01148-12 · Cited by 122
Linheiro, R. S., & Bergman, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030008 · Cited by 122
Large-scale gene trapping in C57BL/6N mouse embryonic stem cellsPreprint
Hansen, G. M., Markesich, D. C., Burnett, M. B., Zhu, Q., Dionne, K. M., Richter, L. J., Finnell, R. H., Sands, A., Zambrowicz, B., & Abuin, A. (2008) · Genome Research · doi:10.1101/gr.078352.108 · Cited by 121
Retroviral DNA integration: HIV and the role of LEDGF/p75.
Ciuffi, A., & Bushman, F. (2006) · Trends in Genetics · doi:10.1016/j.tig.2006.05.006 · Cited by 134
Structural insights into the retroviral DNA integration apparatus
Cherepanov, P., Maertens, G. N., & Hare, S. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.12.005 · Cited by 122
Vranckx, L. S., Demeulemeester, J., Saleh, S., Boll, A., Vansant, G., Schrijvers, R., Weydert, C., Battivelli, E., Verdin, E., Cereseto, A., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.04.039 · Cited by 113
“The WT local palindromic sequence logo surrounding the integration site (Holman and Coffin, 2005; Demeulemeester et al., 2014b)) was maintained in all conditions.”
BackgroundMeekings, K. N., Leipzig, J. N., Bushman, F. D., Taylor, G. P., & Bangham, C. R. M. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000027 · Cited by 113
Structural biology of retroviral DNA integration
Li, X., Krishnan, L., Cherepanov, P., & Engelman, A. (2011) · Virology · doi:10.1016/j.virol.2010.12.008 · Cited by 116
“As examples, HIV-1 preferentially integrates at TDG↓GTWACCHA (Carteau et al., 1998; Holman and Coffin, 2005; Stevens and Griffith, 1996; Wu et al., 2005) whereby PFV favors TD↓VHDBHA (Trobridge et al., 2006; Valkov et al., 2009) (arrows mark scissile phosphodiester bonds; underlines, tDNA…”
BackgroundGenome-wide mapping of foamy virus vector integrations into a human cell line.
Nowrouzi, A., Dittrich, M., Klanke, C., Heinkelein, M., Rammling, M., Dandekar, T., von Kalle, C., & Rethwilm, A. (2006) · Journal of General Virology · doi:10.1099/vir.0.81554-0 · Cited by 113
“The bases of these sequences were numbered from 21000 to 1000 so that the insertion site is located between base 21 and 1, as described by Holman & Coffin (2005) and Wu et al. (2005).”
BackgroundMethodInfluentialWang, H., Jurado, K. A., Wu, X., Shun, M.-C., Li, X., Ferris, A. L., Smith, S. J., Patel, P. A., Fuchs, J. R., Cherepanov, P., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks913 · Cited by 101
“This analysis revealed that the preferred target DNA integration sequence TDG#GTWACCHA (# indicates the position of plus-strand joining) (10,48) was not affected by the presence or absence of either LEDGF/p75 or HRP2 (Supplementary Figure S3).”
BackgroundGillet, N. A., Gutiérrez, G., Rodríguez, S., de Brogniez, A., Renotte, N., Álvarez, I., Trono, K. G., & Willems, L. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003687 · Cited by 96
Retroviral Integrase Structure and DNA Recombination Mechanism
Engelman, A., & Cherepanov, P. (2014) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0024-2014 · Cited by 101
“TCC and STC structures Sequence analysis of retroviral integration sites revealed weakly conserved palindromes that center on the staggered cut in target DNA, indicating that an integrase multimer with dyad symmetry prefers particular nucleotides at the sites of viral DNA joining (158, 159, 160, 161, 162).”
BackgroundThe SET Complex Acts as a Barrier to Autointegration of HIV-1
Yan, N., Cherepanov, P., Daigle, J. E., Engelman, A., & Lieberman, J. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000327 · Cited by 100
“The autointegration sites in the control and knockdown cells showed the same sequence preference as chromosomal integration, favoring insertion within GG dinucleotides (Figure S3) [29,33].”
BackgroundCellular and molecular mechanisms of HIV-1 integration targeting
Engelman, A., & Singh, P. K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2772-5 · Cited by 102
“Retroviral integration favors particular nucleobases at integration sites, although these preferences are rather subtle and thus only become evident through the alignment of multiple sequences [34, 35].”
BackgroundBarr, S. D., Ciuffi, A., Leipzig, J. N., Shinn, P., Ecker, J. R., & Bushman, F. D. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.03.012 · Cited by 89
“Retroviral integration is not strongly sequence-specific with respect to the target DNA at the point of joining [13–16], but integration in vivo shows pronounced favored and disfavored chromosomal regions.”
BackgroundInteractions between Retroviruses and the Host Cell Genome
Poletti, V., & Mavilio, F. (2017) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2017.10.001 · Cited by 85
Shun, M.-C., Botbol, Y., Li, X., Di Nunzio, F., Daigle, J. E., Yan, N., Lieberman, J., Lavigne, M., & Engelman, A. (2008) · Journal of Virology · doi:10.1128/jvi.01561-08 · Cited by 78
“These differences manifest themselves at the level of local DNA sequence (20, 68) and genetic structure (reviewed in reference 2).”
Structure-based prediction of insertion-site preferences of transposons into chromosomes
Geurts, A. M., Hackett, C. S., Bell, J. B., Bergemann, T. L., Collier, L. S., Carlson, C. M., Largaespada, D. A., & Hackett, P. B. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl301 · Cited by 80
The chromatin landscape at the HIV-1 provirus integration site determines viral expression
Vansant, G., Chen, H., Zorita, E. V., Trejbalová, K., Miklík, D., Filion, G. J. P., & Debyser, Z. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa536 · Cited by 79
Retroviral integration site selection
Desfarges, S., & Ciuffi, A. (2010) · Viruses · doi:10.3390/v2010111 · Cited by 78
“In vivo, retroviral integration displayed a weak preference for the primary DNA sequence, similar to the one observed in vitro [60,69,70,72,90,94,96-99].”
BackgroundCrise, B. J., Li, Y., Yuan, C. C., Morcock, D. R., Whitby, D., Munroe, D. J., Arthur, L. O., & Wu, X. (2005) · Journal of Virology · doi:10.1128/jvi.79.19.12199-12204.2005 · Cited by 73
“Additionally, chromatin structure has been suggested to influence integration (13, 24, 25, 30, 44).”
BackgroundIntegration Site Selection by Retroviral Vectors: Molecular Mechanism and Clinical Consequences
Daniel, R., & Smith, J. A. (2008) · Human Gene Therapy · doi:10.1089/hum.2007.148 · Cited by 74
“Finally, careful examination of a large number of integration sites from HIV-1, SIV, MLV, and avian sarcoma-leuko-sis viruses revealed symmetric base preferences surrounding integration sites (Holman and Coffin, 2005; Wu et al ., 2005).”
Integration Profiling of Gene Function With Dense Maps of Transposon Integration
Guo, Y.-B., Park, J.-M., Cui, B.-W., Humes, E., Gangadharan, S., Hung, S., FitzGerald, P., Hoe, K.-L., Grewal, S., Craig, N., et al. (2013) · Genetics · doi:10.1534/genetics.113.152744 · Cited by 62
What Integration Sites Tell Us about HIV Persistence
Hughes, S. H., & Coffin, J. M. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.04.010 · Cited by 74
Self-citationUse of HIV as a gene transfer vector.
Pluta, K. D., & Kacprzak, M. M. (2009) · Acta Biochimica Polonica · doi:10.18388/abp.2009_2490 · Cited by 76
“Wu et al. (2005) and Holman and Coffin (2005) have examined a large number of integration site sequences from various retroviruses, including HIV-1, and found that they are palindromic in nature.”
BackgroundHIV DNA is heavily uracilated, which protects it from autointegration
Yan, N., O’Day, E. M., Wheeler, L. A., Engelman, A., & Lieberman, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102943108 · Cited by 70
“HIV IN favors integration (for both integration and autointegration) (10, 42, 43) into target DNAs at sites that loosely match an 11-bp consensus sequence containing approximately four to seven thymidines.”
BackgroundPapayannakos, C. J., & Daniel, R. (2012) · Gene Therapy · doi:10.1038/gt.2012.88 · Cited by 68
Ciuffi, A., Mitchell, R. S., Hoffmann, C., Leipzig, J. N., Shinn, P., Ecker, J. R., & Bushman, F. D. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.10.009 · Cited by 66
Key determinants of target DNA recognition by retroviral intasomes
Serrao, E., Ballandras-Colas, A., Cherepanov, P., Maertens, G. N., & Engelman, A. N. (2015) · Retrovirology · doi:10.1186/s12977-015-0167-3 · Cited by 62
“Rev-A is of particular interest, as it is a gammaretrovirus with a 5 bp TSD; all other gammaretroviruses yield 4 bp TSDs [14,15,17].”
BackgroundInfluentialSerrao, E., Krishnan, L., Shun, M.-C., Li, X., Cherepanov, P., Engelman, A., & Maertens, G. N. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku136 · Cited by 59
“Based on these observations, we hypothesized that HIV-1 IN amino acids that interact with tDNA bases could be identified by comparing integration sites of mutant IN enzymes to the canonical integration sequence (–3)TDG#(G/V)TWA(C/B)CHA(7) (written using standard International Union of Biochemistry base codes; the vert…”
InfluentialMolecular Studies of HTLV-1 Replication: An Update
Martin, J., Maldonado, J. O., Mueller, J. D., Zhang, W., & Mansky, L. M. (2016) · Viruses · doi:10.3390/v8020031 · Cited by 77
“It has been found that HTLV-1 integrates into the genome in the absence of preferred sites [45–50].”
BackgroundHackett, C. S., Geurts, A. M., & Hackett, P. B. (2007) · Genome biology · doi:10.1186/gb-2007-8-s1-s12 · Cited by 63
“both transposons [115,124,130,131] and retroviruses [111,126] to determine general characteristics of the flanking sequence of ‘preferred’ integration sites.”
BackgroundCiuffi, A., Diamond, T. L., Hwang, Y. S., Marshall, H. M., & Bushman, F. D. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.960 · Cited by 67
Moalic, Y., Blanchard, Y., Felix, H. S., & Jestin, A. (2006) · Journal of Virology · doi:10.1128/jvi.00904-06 · Cited by 56
“This has been demonstrated experimentally in an assay of ASLV retroviral integration with a quail inducible metallothionein gene.”
BackgroundMethodInfluentialIntasome architecture and chromatin density modulate retroviral integration into nucleosome
Benleulmi, M. S., Matysiak, J., Henriquez, D. R., Vaillant, C., Lesbats, P., Calmels, C., Naughtin, M., Leon, O., Skalka, A. M., Ruff, M., et al. (2015) · Retrovirology · doi:10.1186/s12977-015-0145-9 · Cited by 47
“On the other hand, cellular data obtained from a murine LEDGF/p75 knock-out (KO) model have shown that LEDGF/p75 was not involved in the local target DNA sequence preference associated with HIV-1 integration [32-34].”
BackgroundAmplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites
Serrao, E., Cherepanov, P., & Engelman, A. (2016) · Journal of Visualized Experiments · doi:10.3791/53840 · Cited by 63
Coffin, J. M., Bale, M. J., Wells, D., Guo, S., Luke, B. T., Zerbato, J. M., Sobolewski, M. D., Sia, T., Shao, W., Wu, X., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009141 · Cited by 59
“Retroviral integration exhibits a modest preference for specific bases around the site of integration [10, 11], and there is no discernable preference for the integration of the viral DNA in either orientation relative to the direction of transcription of the target gene [7, 12, 13].”
Self-citationMacNeil, A., Sankalé, J.-L., Meloni, S., Sarr, A. D., Mboup, S., & Kanki, P. J. (2006) · Journal of Virology · doi:10.1128/jvi.00604-06 · Cited by 51
“Although integration site selection does not occur in a sequence-specific manner, recent studies have indicated that retrovirus integration favors palindromic sequences and that distinct genomic sequences are favored in a retrovirus species-specific manner (15, 42).”
BackgroundRetroviral Vectors: Post Entry Events and Genomic Alterations
Nowrouzi, A., Glimm, H., Kalle, C. V., & Schmidt, M. (2011) · Viruses · doi:10.3390/v3050429 · Cited by 48
“Most DNA sequences can act as integration acceptor sites, however, recent large scale studies on the integration site consensus of retroviruses in vivo [15,52,53] and in vitro [46,47] have shown that the base composition at retroviral target sites is biased for preferences or avoidances of”
BackgroundDiehl, W. E., Patel, N., Halm, K., & Johnson, W. E. (2016) · eLife · doi:10.7554/elife.12704 · Cited by 47
Integration Site Choice of a Feline Immunodeficiency Virus Vector
Kang, Y.-B., Moressi, C. J., Scheetz, T., Xie, L.-T., Tran, D., Casavant, T., Ak, P., Benham, C., Davidson, B., & McCray, P. (2006) · Journal of Virology · doi:10.1128/jvi.00719-06 · Cited by 53
“Overall, FIV integration preferences were similar to those reported for HIV (19) and SIV (6) and distinct from those reported for MLV, ASLV (17, 26), and FV (23).”
BackgroundMethodInfluentialDNA double strand break repair enzymes function at multiple steps in retroviral infection
Sakurai, Y., Komatsu, K., Agematsu, K., & Matsuoka, M. (2009) · Retrovirology · doi:10.1186/1742-4690-6-114 · Cited by 46
Understanding retroviral life cycle and its genomic RNA packaging
Chameettachal, A., Mustafa, F., & Rizvi, T. A. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167924 · Cited by 41
Liu, H., Dow, E. C., Arora, R., Kimata, J. T., Bull–Otterson, L., Arduino, R. C., & Rice, A. P. (2006) · Journal of Virology · doi:10.1128/jvi.00542-06 · Cited by 40
The Base Excision Repair Pathway Is Required for Efficient Lentivirus Integration
Yoder, K. E., Espeseth, A. S., Wang, X.-H., Fang, Q., Russo, M. T., Lloyd, R. S., Hazuda, D. J., Sobol, R. W., & Fishel, R. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017862 · Cited by 45
“Retroviral integration sites display a subtle sequence preference unique to each virus”
BackgroundB′-protein phosphatase 2A is a functional binding partner of delta-retroviral integrase
Maertens, G. N. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1347 · Cited by 38
“Alignments of experimentally determined integration sites uncovered weakly conserved palindromic DNA consensus sequences (3,6-10).”
Henzy, J. E., Gifford, R. J., Johnson, W. E., & Coffin, J. M. (2013) · Journal of Virology · doi:10.1128/jvi.02863-13 · Cited by 38
Self-citationDelelis, O., Parissi, V., Leh, H., Mbemba, G., Petit, C., Sonigo, P., Deprez, E., & Mouscadet, J. F. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000608 · Cited by 35
Retroviral intasomes search for a target DNA by 1D diffusion which rarely results in integration
Jones, N. D., Lopez, M. A., Hanne, J., Peake, M. B., Lee, J., Fishel, R. A., & Yoder, K. E. (2016) · Nature Communications · doi:10.1038/ncomms11409 · Cited by 33
Retroviruses integrate into a shared, non-palindromic DNA motif
Kirk, P., Huvet, M., Melamed, A., Maertens, G. N., & Bangham, C. R. M. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.212 · Cited by 38
Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges
Yoder, K. E., Rabe, A. J., Fishel, R. A., & Larue, R. C. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.662331 · Cited by 37
Human T-Lymphotropic Virus (HTLV): Epidemiology, Genetic, Pathogenesis, and Future Challenges
Branda, F., Romano, C., Pavia, G., Bilotta, V., Locci, C., Azzena, I., Deplano, I., Pascale, N., Perra, M. T., Giovanetti, M., et al. (2025) · Viruses · doi:10.3390/v17050664 · Cited by 37
Impact of LEDGIN treatment during virus production on residual HIV-1 transcription
Vansant, G., Vranckx, L. S., Zurnic, I., Looveren, D. V., de Velde, P. V., Nobles, C. L., Gijsbers, R., Christ, F., & Debyser, Z. (2019) · Retrovirology · doi:10.1186/s12977-019-0472-3 · Cited by 33
Molecular Biology and Diversification of Human Retroviruses
Meissner, M. E., Talledge, N., & Mansky, L. M. (2022) · Frontiers in Virology · doi:10.3389/fviro.2022.872599 · Cited by 36
Doolittle‐Hall, J., Glasspoole, D. L. C., Seaman, W. T., & Webster-Cyriaque, J. Y. (2015) · Cancers · doi:10.3390/cancers7040887 · Cited by 32
“HIV a d other integrase-dependent lem nts have prefe red sequence motifs at their integration sites [1,38,39].”
BackgroundMullins, J. I., & Frenkel, L. M. (2017) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiw636 · Cited by 29
Matrix attachment regions as targets for retroviral integration
Johnson, C., & Levy, L. S. (2005) · Virology Journal · doi:10.1186/1743-422x-2-68 · Cited by 30
“Accumulating evidence indicates that retroviral integration site selection is influenced by properties of cellular DNA structure [11,21-24].”
BackgroundEngineered Sleeping Beauty transposase redirects transposon integration away from genes
Miskey, C., Kesselring, L., Querques, I., Abrusán, G., Barábas, O., & Ivics, Z. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac092 · Cited by 29
Integration of retroviral vectors
Gabriel, R., Schmidt, M., & Kalle, C. V. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.08.006 · Cited by 33
“However, weak palindromic consensus sequences are commonly found at retroviral IS [21,22].”
BackgroundSites of retroviral DNA integration: From basic research to clinical applications
Serrao, E., & Engelman, A. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2015.1102859 · Cited by 32
Mapping DNase-I hypersensitive sites on human isochores
Filippo, M. D., & Bernardi, G. (2008) · Gene · doi:10.1016/j.gene.2008.02.012 · Cited by 28
Structural and sequencing analysis of local target DNA recognition by MLV integrase
Aiyer, S., Rossi, P., Malani, N., Schneider, W. M., Chandar, A., Bushman, F. D., Montelione, G. T., & Roth, M. J. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv410 · Cited by 25
“MLV, PFV and HIV display distinct local sequence preferences at the site of integration (63,64).”
BackgroundCommon Viral Integration Sites Identified in Avian Leukosis Virus-Induced B-Cell Lymphomas
Justice, J., Morgan, R. W., & BEEMON, K. L. (2015) · mBio · doi:10.1128/mbio.01863-15 · Cited by 27
“This contrasts with other retroviruses such as HIV and murine leukemia virus (MLV) that have perfectly symmetric consensus sequences (5, 6).”
BackgroundResultHotspots of MLV integration in the hematopoietic tumor genome
Tsuruyama, T., Hiratsuka, T., & Yamada, N. (2016) · Oncogene · doi:10.1038/onc.2016.285 · Cited by 26
D’Urbano, V., Crignis, E. D., & Re, M. C. (2018) · Current HIV Research · doi:10.2174/1570162x16666180817115830 · Cited by 31
Serial number tagging reveals a prominent sequence preference of retrotransposon integration
Chatterjee, A. G., Esnault, C., Guo, Y., Hung, S., McQueen, P. G., & Levin, H. L. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku534 · Cited by 27
HIV-1 Integrase-DNA Recognition Mechanisms
Kessl, J. J., McKee, C. J., Eidahl, J. O., Shkriabai, N., Katz, A., & Kvaratskhelia, M. (2009) · Viruses · doi:10.3390/v1030713 · Cited by 27
“integration sites [101–107].”
Engineering Next-Generation BET-Independent MLV Vectors for Safer Gene Therapy
Ashkar, S. E., Looveren, D. V., Schenk, F., Vranckx, L. S., Demeulemeester, J., Rijck, J. D., Debyser, Z., Modlich, U., & Gijsbers, R. (2017) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2017.04.002 · Cited by 24
“This local integration site sequence is mainly determined by IN contacts with the (nucleosomal) DNA template.(40,41) To assess whether the addition of alternative”
BackgroundVranckx, L. S., Demeulemeester, J., Debyser, Z., & Gijsbers, R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164167 · Cited by 24
The Multifaceted Contributions of Chromatin to HIV-1 Integration, Transcription, and Latency
Crignis, E. D., & Mahmoudi, T. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.08.006 · Cited by 23
“…has not been identified, a certain degree of bias into integration site selection results from the presence of palindromic sequences within the target DNA, which are associated with higher bendability and thus are a preferential site for integration (Grandgenett, 2005; Holman and Coffin, 2005).”
Background
Metadata
- Authors
- Holman, A. G., & Coffin, J. M.
- Affiliations
- Tufts University (US)
- Corresponding author
- Coffin, John M.
- ORCID
- Coffin, John M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-03-31
- Volume
- 102
- Issue
- 17
- Pages
- 6103-6107
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1087937
- OpenAlex
- W2026422480
- Cited by
- 164
- References
- 12
- Citations by year
- 2026: 1 · 2025: 4 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 17 · 2015: 11 · 2014: 7 · 2013: 7 · 2012: 12
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Update notices
- correction (2005-04-26)
- Open access
- green
- dx.doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- F. M. Kirby Foundation
- University of Pennsylvania
- James N. Kirby Foundation
- National Institutes of Health (NIH T32)
- National Human Genome Research Institute
- National Cancer Institute (T32 CA65441, T32CA065441, R01-CA-92192, R01CA092192)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- retroviral integration, integration site selection, HIV-1, murine leukemia virus, host cell DNA, sequence symmetry
- MeSH terms
- Alpharetrovirus, Base Composition, Base Sequence, Cloning, Molecular, HeLa Cells, Humans, HIV-1, Virus Integration
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