Repair of gaps in retroviral DNA integration intermediates
Open accessAbstract
Diverse mobile DNA elements are believed to pirate host cell enzymes to complete DNA transfer. Prominent examples are provided by retroviral cDNA integration and transposon insertion. These reactions initially involve the attachment of each element 3′ DNA end to staggered sites in the host DNA by element-encoded integrase or transposase enzymes. Unfolding of such intermediates yields DNA gaps at each junction. It has been widely assumed that host DNA repair enzymes complete attachment of the remaining DNA ends, but the enzymes involved have not been identified for any system. We have synthesized DNA substrates containing the expected gap and 5′ two-base flap structure present in retroviral integration intermediates and tested candidate enzymes for the ability to support repair in vitro. We find three required activities, two of which can be satisfied by multiple enzymes. These are a polymerase (polymerase beta, polymerase delta and its cofactor PCNA, or reverse transcriptase), a nuclease (flap endonuclease), and a ligase (ligase I, III, or IV and its cofactor XRCC4). A proposed pathway involving retroviral integrase and reverse transcriptase did not carry out repair under the conditions tested. In addition, prebinding of integrase protein to gapped DNA inhibited repair reactions, indicating that gap repair in vivo may require active disassembly of the integrase complex.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During repair of single-stranded gaps, primarily cellular enzymes and to a certain extent RT and IN remove the two unpaired nucleotides from the 5′ ends of viral DNA and repair the gaps.
“During the repair of the single-stranded gaps, primarily cellular enzymes, and to a certain extent RT and IN, are responsible for removing the two unpaired nucleotides from the 5′ ends of the viral DNA and repairing the single-stranded gaps (Acel et al. 1998, Yoder and Bushman 2000).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Yoder and Bushman 2000
Cites
Retroviral DNA integration directed by HIV integration protein in vitro
Bushman, F. D., Fujiwara, T., & Craigie, R. (1990) · Science · doi:10.1126/science.2171144 · Cited by 338 · see citing works
Self-citationKatzman, M., Katz, R. A., Skalka, A. M., & Leis, J. (1989) · Journal of Virology · doi:10.1128/jvi.63.12.5319-5327.1989 · Cited by 311 · see citing works
A large nucleoprotein assembly at the ends of the viral DNA mediates retroviral DNA integration
Wei, S., Mizuuchi, K., & Craigie, R. (1997) · The EMBO Journal · doi:10.1093/emboj/16.24.7511 · Cited by 102 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Genome-Scale RNAi Screen for Host Factors Required for HIV Replication
Zhou, H., Xu, M., Huang, Q., Gates, A. T., Zhang, X. D., Castle, J. C., Stec, E. M., Ferrer, M., Strulovici, B., Hazuda, D. J., et al. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.10.004 · Cited by 784 · see citing works
“This observation supports a role for DNA repair pathways in HIV infection (Yoder and Bushman, 2000; Skalka and Katz, 2005).”
ResultIntegrase inhibitors to treat HIV/Aids
Pommier, Y., Johnson, A. A., & Marchand, C. (2005) · Nature reviews. Drug discovery · doi:10.1038/nrd1660 · Cited by 693 · see citing works
“It is likely that cellular enzymes/ pathways are involved in this 5′-processing, although their identity remains uncertai”
BackgroundRole of the non‐homologous DNA end joining pathway in the early steps of retroviral infection
Li, L., Olvera, J. M., Yoder, K., Mitchell, R., Butler, S., Lieber, M., Martin, S. L., & Bushman, F. D. (2001) · EMBO Journal · doi:10.1093/emboj/20.12.3272 · Cited by 386 · see citing works
Self-citationCraigie, R., & Bushman, F. D. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006890 · Cited by 327 · see citing works
Self-citationHIV Integrase, a Brief Overview from Chemistry to Therapeutics*
Craigie, R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r100027200 · Cited by 277 · see citing works
Cellular co-factors of HIV-1 integration.
Maele, B. V., Busschots, K., Vandekerckhove, L., Christ, F., & Debyser, Z. (2006) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/j.tibs.2005.12.002 · Cited by 204 · see citing works
“This repair is probably accomplished by host-cell DNA-repair enzymes [ 3 ].”
BackgroundGenomes in conflict: maintaining genome integrity during virus infection.
Weitzman, M., Lilley, C., & Chaurushiya, M. S. (2010) · Annual Review of Microbiology · doi:10.1146/annurev.micro.112408.134016 · Cited by 201 · see citing works
Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy.
Mccoll, D., & Chen, X.-W. (2010) · Antiviral Research · doi:10.1016/j.antiviral.2009.11.004 · Cited by 187 · see citing works
Human cell proteins and human immunodeficiency virus DNA integration
Turlure, F. (2004) · Frontiers in bioscience · doi:10.2741/1472 · Cited by 156 · see citing works
“Experiments with oligonucleotide substrates that mimicked one side of the gapped HIV-1 structure demonstrated that a variety of DNA polymerases including polymerase beta, delta, or HIV-1 reverse transcriptase could fulfill the requirements of step (i), that flap endonuclease I effectively removed the non-templated 5'…”
BackgroundZhu, K., Dobard, C., & Chow, S. A. (2004) · Journal of Virology · doi:10.1128/jvi.78.10.5045-5055.2004 · Cited by 158 · see citing works
“Host enzymes are believed to carry out the repair of gaps between viral and host DNAs after strand transfer (6, 14, 60), resulting in the formation of a provirus.”
BackgroundNucleocapsid protein function in early infection processes
Thomas, J. A., & Gorelick, R. J. (2008) · Virus Research · doi:10.1016/j.virusres.2007.12.006 · Cited by 162 · see citing works
“This process is thought to be mediated by cellular repair enzymes (Brown, 1997;Yoder and Bushman, 2000).”
BackgroundLesbats, P., Engelman, A., & Cherepanov, P. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00125 · Cited by 232 · see citing works
Integrase, LEDGF/p75 and HIV replication
Poeschla, E. M. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7540-5 · Cited by 127 · see citing works
Mostoslavsky, G., Kotton, D. N., Fabian, A., Gray, J., Lee, J.-S., & Mulligan, R. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.01.005 · Cited by 147 · see citing works
Maele, B. V., Rijck, J. D., de Clercq, E., & Debyser, Z. (2003) · Journal of Virology · doi:10.1128/jvi.77.8.4685-4694.2003 · Cited by 140 · see citing works
“Repair of the 5-base single-stranded DNA gaps between the 5 ends of the viral DNA and the 3 ends of the host DNA is likely carried out by host cell enzymes (4, 49).”
BackgroundViral manipulation of DNA repair and cell cycle checkpoints
Chaurushiya, M. S., & Weitzman, M. D. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.04.016 · Cited by 120 · see citing works
“In vitro studies have demonstrated that flap endonuclease and multiple ligases can repair a gapped DNA substrate [77,78].”
BackgroundRetroviral 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 · see citing works
“The third step of integration is thought to involve host DNA repair proteins to remove the two nucleotide overhang and to fill in the DNA gaps [ 9 ].”
BackgroundSelf-citationRetroviral 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 137 · see citing works
“Consistent with this, known gap repair enzymes have been shown to act on model host-virus DNA junctions in vitro (Yoder and Bushman, 2000).”
BackgroundSelf-citationGao, K., Butler, S., & Bushman, F. (2001) · EMBO Journal · doi:10.1093/emboj/20.13.3565 · Cited by 133 · see citing works
Self-citationRaltegravir: the first HIV type 1 integrase inhibitor.
Hicks, C., & Gulick, R. (2009) · Clinical Infectious Diseases · doi:10.1086/597290 · Cited by 131 · see citing works
Integrase-defective lentiviral vectors: Progress and applications
Banasik, M. B., & McCray, P. B. (2010) · Gene Therapy · doi:10.1038/gt.2009.135 · Cited by 129 · see citing works
Ariumi, Y., Turelli, P., Masutani, M., & Trono, D. (2005) · Journal of Virology · doi:10.1128/jvi.79.5.2973-2978.2005 · Cited by 127 · see citing works
“In vitro experiments indicate that cellular DNA polymerase and DNA ligase can mediate this process (27).”
BackgroundRoles of host cell factors in circularization of retroviral dna
Kilzer, J. M., Stracker, T. H., Beitzel, B. F., Meek, K., Weitzman, M. D., & Bushman, F. D. (2003) · Virology · doi:10.1016/s0042-6822(03)00455-0 · Cited by 123 · see citing works
“This reaction can be modeled in vitro with known cellular gap repair enzymes (Yoder and Bushman, 2000), though the factors active during infection in vivo have not been fully clarified.”
Self-citationInteractions of viruses with the cellular DNA repair machinery
Weitzman, M. D., Carson, C. T., Schwartz, R. A., & Lilley, C. E. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.03.018 · Cited by 104 · see citing works
Goff, S. P. (2001) · The Journal of Gene Medicine · doi:10.1002/1521-2254(200111)3:6 · Cited by 119 · see citing works
Structure and function of retroviral integrase
Maertens, G. N., Engelman, A. N., & Cherepanov, P. (2022) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00586-9 · Cited by 124 · see citing works
Svarovskaia, E., Barr, R., Zhang, X.-C., Pais, G., Marchand, C., Pommier, Y., Burke, T. R., & Pathak, V. (2004) · Journal of Virology · doi:10.1128/jvi.78.7.3210-3222.2004 · Cited by 124 · see citing works
“Host cell enzymes are implicated in filling the gaps at the site of integration and removing unpaired dinucleotides from the viral DNA ends to complete the integration reaction (4, 11, 12, 68).”
BackgroundHIV-1 IN Inhibitors: 2010 Update and Perspectives
Marchand, C., Maddali, K., Métifiot, M., & Pommier, Y. (2009) · Current Topics in Medicinal Chemistry · doi:10.2174/156802609789630910 · Cited by 122 · see citing works
Limón, A., Devroe, E., Lu, R. Q., Ghory, H., Silver, P., & Engelman, A. (2002) · Journal of Virology · doi:10.1128/jvi.76.21.10598-10607.2002 · Cited by 115 · see citing works
“The final step of the integration process, which involves repairing the gaps between the unjoined viral 5 ends and the chromosome, can be completed by host cell enzymes (4, 54 ).”
BackgroundInteraction of HIV-1 Integrase with DNA Repair Protein hRad18
Mulder, L. C. F., Chakrabarti, L. A., & Muesing, M. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203061200 · Cited by 86 · see citing works
Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response
Daniel, R., Kao, G. D., Taganov, K. D., Greger, J., Favorova, O. O., Merkel, G. W., Yen, T. J., Katz, R. A., & Skalka, A. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730887100 · Cited by 100 · see citing works
New class of HIV integrase inhibitors that block viral replication in cell culture.
Pannecouque, C., Pluymers, W., Maele, B. V., Tetz, V., Cherepanov, P., de Clercq, E., Witvrouw, M., & Debyser, Z. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00952-1 · Cited by 106 · see citing works
The 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 90 · see citing works
“Although there are reports that other DNA repair factors either facilitate or inhibit HIV-1 infection, most of these have been postulated to influence 2-LTR circle formation or 59 gap repair and to act at a later stage of infection in the nucleus [3,39–43].”
BackgroundStructural basis for HIV‐1 DNA integration in the human genome, role of the LEDGF/P75 cofactor
Michel, F., Crucifix, C., Granger, F., Eiler, S., Mouscadet, J., Korolev, S., Agapkina, J., Ziganshin, R., Gottikh, M., Nazabal, A., et al. (2009) · EMBO Journal · doi:10.1038/emboj.2009.41 · Cited by 98 · see citing works
“Host DNA repair proteins remove the two nucleotide overhang and fill in the DNA gaps to complete the integration reaction (Yoder and Bushman, 2000).”
BackgroundMousnier, A., Kubat, N. J., Massias-Simon, A., Ségéral, E., Rain, J., Benarous, R., Emiliani, S., & Dargemont, C. (2007) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0705162104 · Cited by 97 · see citing works
Retroviruses and yeast retrotransposons use overlapping sets of host genes.Preprint
Irwin, B., Aye, M., Baldi, P., Beliakova-Bethell, N., Cheng, H., Dou, Y.-M., Liou, W., & Sandmeyer, S. (2005) · Genome Research · doi:10.1101/gr.3739005 · Cited by 93 · see citing works
“1997) and contains gaps and displaced single-stranded regions (Yoder and Bushman 2000).”
BackgroundFikkert, V., Maele, B. V., Vercammen, J., Hantson, A., Remoortel, B. V., Michiels, M., Gurnari, C., Pannecouque, C., de Maeyer, M., Engelborghs, Y., et al. (2003) · Journal of Virology · doi:10.1128/jvi.77.21.11459-11470.2003 · Cited by 93 · see citing works
“This repair is probably accomplished by host cell DNA repair enzymes, although retroviral enzymes have been implicated as well (8, 36).”
BackgroundIntegrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs
Smith, S. J., Zhao, X. Z., Passos, D. O., Lyumkis, D., Burke, T. R., & Hughes, S. H. (2021) · Viruses · doi:10.3390/v13020205 · Cited by 110 · see citing works
“The integration reaction leaves a nick and a short mismatch with the host DNA, which are repaired by host DNA repair enzymes [38,39].”
BackgroundChromatin-Associated Genes Protect the Yeast Genome From Ty1 Insertional Mutagenesis
Nyswaner, K. M., Checkley, M. A., Yi, M., Stephens, R. M., & Garfinkel, D. J. (2008) · Genetics · doi:10.1534/genetics.107.082602 · Cited by 90 · see citing works
“…mammalian genes required for DNA repair, genome maintenance, and protein trafficking that also modulate retroviral replication and virion budding (Yoder and Bushman 2000; Li et al. 2001; Kilzer et al. 2003; Aye et al. 2004; Lau et al. 2004; Irwin et al. 2005; BeliakovaBethell et al. 2006; Lloyd…”
BackgroundYant, S., & Kay, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.23.8505-8518.2003 · Cited by 88 · see citing works
“for retroviral integrase (67), investigations into the require-”
BackgroundBonnenfant, S., Thomas, C., Vita, C., Subra, F., Deprez, E., Zouhiri, F., Desmaële, D., d'Angelo, J., Mouscadet, J., & Leh, H. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5728-5736.2004 · Cited by 84 · see citing works
“Although gap repair is believed to be carried out by cellular proteins (15, 35, 51), both 3 end processing and strand transfer are primarily mediated by the viral”
BackgroundFikkert, V., Hombrouck, A., Remoortel, B. V., de Maeyer, M., Pannecouque, C., de Clercq, E., Debyser, Z., & Witvrouw, M. (2004) · AIDS (London) · doi:10.1097/00002030-200410210-00006 · Cited by 78 · see citing works
“repair enzymes probably accomplish this repair, although retroviral enzymes have been implicated as well [7,8].”
BackgroundMargot, N., Hluhanich, R. M., Jones, G. S., Andreatta, K., Tsiang, M., Mccoll, D., White, K., & Miller, M. D. (2012) · Antiviral Research · doi:10.1016/j.antiviral.2011.12.008 · Cited by 73 · see citing works
Suzuki, Y., & Craigie, R. (2002) · Journal of Virology · doi:10.1128/jvi.76.23.12376-12380.2002 · Cited by 73 · see citing works
“This integration step is essential in the retroviral replication cycle (1, 3, 8, 18, 19, 20) and comprises 3 -end processing, strand transfer, and gap repair measures in vivo (5, 10, 16, 30).”
BackgroundHIV Integrase Inhibitors: 20-Year Landmark and Challenges
Métifiot, M., Marchand, C., & Pommier, Y. (2013) · Advances in Pharmacology · doi:10.1016/b978-0-12-405880-4.00003-2 · Cited by 72 · see citing works
“The importance of BER for proviral gap joining is consistent with earlier biochemical studies (Yoder & Bushman, 2000).”
BackgroundResultCiuffi, A., Diamond, T. L., Hwang, Y., Marshall, H. M., & Bushman, F. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.ft-232 · Cited by 71 · see citing works
“The joining of the second DNA strand at each end and removal of the 5 (cid:2) overhang is probably carried out by the host cell enzymes that normally repair DNA gaps (Yoder and Bushman, 2000).”
Self-citationHwang, Y., Rhodes, D., & Bushman, F. D. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.24.4884 · Cited by 70 · see citing works
“The terminal cleavage and strand transfer reactions can be modeled in reactions containing purified integrase (22–27) and the gap filling and ligation reactions can be modeled with purified DNA repair enzymes (21).”
BackgroundSelf-citationEsposito, F., & Tramontano, E. (2014) · Antiviral Chemistry and Chemotherapy · doi:10.3851/imp2690 · Cited by 68 · see citing works
Zamborlini, A., Coiffic, A., Beauclair, G., Delelis, O., Paris, J., Koh, Y., Magne, F., Giron, M.-L., Tobaly-Tapiero, J., Deprez, E., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.189274 · Cited by 63 · see citing works
“In the viral context, IN degradation seems to occur after integration and to be required for correct gap repair (29-30) and viral genes expression (26).”
BackgroundToolbox for retrovectorologists
Pagès, J., & Bru, T. (2004) · Journal of Gene Medicine · doi:10.1002/jgm.498 · Cited by 60 · see citing works
“Cleavage and ligation to the host genome uses a strand exchange process leaving two single-stranded repeats that are filled by the host DNA repair machinery [44].”
BackgroundIntegration site selection by lentiviruses: biology and possible control.
Bushman, F. D. (2002) · Current Topics in Microbiology and Immunology · doi:10.1007/978-3-642-56114-6_8 · Cited by 58 · see citing works
Self-citationIntegrase inhibitors effective against human T-cell leukemia virus type 1
Seegulam, M. E., & Ratner, L. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1186/1742-4690-8-s1-a34 · Cited by 54
“Integrase catalyzes the insertion of viral cDNA in three stages: complex assembly, 3 processing, and strand transfer (5, 24).”
Katlama, C., & Murphy, R. (2009) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s3137 · Cited by 54 · see citing works
The Hunt for HIV-1 Integrase Inhibitors
Lataillade, M., & Kozal, M. (2006) · AIDS Patients Care and STDs · doi:10.1089/apc.2006.20.489 · Cited by 54 · see citing works
“18,32 Although IN may be involved in these repair reactions, it is not necessary because the host cell already has the machinery to carry out such processes.”
Deciphering the Code for Retroviral Integration Target Site Selection
Santoni, F. A., Hartley, O., & Luban, J. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001008 · Cited by 53 · see citing works
“The remaining free ends of the viral DNA are then repaired by host enzymes [19–21].”
BackgroundEspeseth, A. S., Fishel, R., Hazuda, D., Huang, Q., Xu, M., Yoder, K., & Zhou, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017612 · Cited by 50 · see citing works
“Although long path BER enzymes have been used to model repair of HIV integration intermediates in vitro [15], siRNAs targeting these genes had little effect on HIV infection (Figure 1C and Table 1).”
MethodSelf-citationJohn, S., Fletcher, T. M., & Jonsson, C. (2005) · Journal of biomolecular screening · doi:10.1177/1087057105276318 · Cited by 50 · see citing works
Host Factors in Retroviral Integration and the Selection of Integration Target Sites
Craigie, R., & Bushman, F. D. (2014) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0026-2014 · Cited by 45 · see citing works
“Cocktails of host-encoded DNA repair enzymes have been shown to be able to carry out the needed polymerization, branch excision, and ligation steps in vitro on substrate DNAs modeling the expected gaps (118).”
BackgroundSelf-citationSingle-particle image reconstruction of a tetramer of HIV integrase bound to DNA.
Ren, G., Gao, K., Bushman, F., & Yeager, M. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.11.029 · Cited by 49 · see citing works
Self-citationThe Roles of Cellular Factors in Retroviral Integration
Engelman, A. (2003) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-19012-4_6 · Cited by 45 · see citing works
“1997), and cellular factors (Daniel et al. 1999; Brin et al. 2000; Yoder and Bushman 2000; Ha et al. 2001) have been implicated in these repair processes.”
BackgroundThe Ataxia Telangiectasia-Mutated and Rad3-Related Protein Is Dispensable for Retroviral Integration
DeHart, J., Andersen, J., Zimmerman, E., Ardon, O., An, D.-S., Blackett, J., Kim, B., & Planelles, V. (2005) · Journal of Virology · doi:10.1128/jvi.79.3.1389-1396.2005 · Cited by 47 · see citing works
“found that various combinations of cellular enzymes with redundant activities (DNA polymerases beta and delta; DNA ligases I, III, and IV; and flap endonuclease) were competent for repair of synthetic viralcellular DNA junctions in vitro (40).”
BackgroundProgress in HIV-1 Integrase Inhibitors: A Review of their Chemical Structure Diversity
Hajimahdi, Z., & Zarghi, A. (2016) · Iranian journal of pharmaceutical research · doi:10.22037/ijpr.2016.1935 · Cited by 47
NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase
Knyazhanskaya, E., Anisenko, A., Shadrina, O., Kalinina, A., Zatsepin, T., Zalevsky, A., Mazurov, D., & Gottikh, M. (2019) · Retrovirology · doi:10.1186/s12977-019-0492-z · Cited by 46 · see citing works
Inhibiting the HIV Integration Process: Past, Present, and the Future
Santo, R. D. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400674a · Cited by 99 · see citing works
Methods for integration site distribution analyses in animal cell genomes
Ciuffi, A., Ronen, K., Brady, T. L., Malani, N., Wang, G. J., Berry, C., & Bushman, F. (2008) · Methods · doi:10.1016/j.ymeth.2008.10.028 · Cited by 46 · see citing works
Self-citationEffect of DNA Repair Protein Rad18 on Viral Infection
Lloyd, A. G., Tateishi, S., Bieniasz, P., Muesing, M., Yamaizumi, M., & Mulder, L. C. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020040 · Cited by 46 · see citing works
“Mechanisms that have been proposed to be involved in DNA repair and DNA metabolism during retroviral integration include: base excision repair [2,3], homologous recombination (HR) [4] and non-homologous end joining [5–8].”
BackgroundPfeiffer, J. K., & Telesnitsky, A. (2001) · Journal of Virology · doi:10.1128/jvi.75.23.11263-11274.2001 · Cited by 46 · see citing works
“There is evidence in the literature for a premature jump during second-strand transfer (25, 29, 30), and emerging evidence that host factors may complete provirus structures during viral replication (54).”
BackgroundBiochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase
Dar, M. J., Monel, B., Krishnan, L., Shun, M.-C., Nunzio, F. D., Helland, D. E., & Engelman, A. (2009) · Retrovirology · doi:10.1186/1742-4690-6-94 · Cited by 37 · see citing works
“The final step, repair of single stranded gaps and joining of viral DNA 5' ends, is accomplished by cellular enzymes [5,6].”
Retroviral Vectors: Post Entry Events and Genomic Alterations
Nowrouzi, A., Glimm, H., von Kalle, C., & Schmidt, M. (2011) · Viruses · doi:10.3390/v3050429 · Cited by 43 · see citing works
“cellular components [51] results in a direct duplication of 4–5 base pairs flanking the integrated viral DNA [2].”
BackgroundPeptides that inhibit HIV‐1 integrase by blocking its protein–protein interactions
Maes, M., Loyter, A., & Friedler, A. (2012) · The FEBS Journal · doi:10.1111/j.1742-4658.2012.08680.x · Cited by 42 · see citing works
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 · see citing works
Robert, I., Karicheva, O., Martin, B. R. S., Schreiber, V., & Dantzer, F. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.02.001 · Cited by 40 · see citing works
Integrase Inhibitors: A Novel Class of Antiretroviral Agents
Schafer, J., & Squires, K. (2010) · The Annals of Pharmacotherapy · doi:10.1345/aph.1m309 · Cited by 40 · see citing works
Passaes, C. P. B., Guimarães, M. L., Fernandez, S., Lorete, R. D. S., Teixeira, S., Fernandez, J. C. C., & Morgado, M. (2009) · Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0b013e31819df3b3 · Cited by 40 · see citing works
“Integration is most likely completed by the host DNA repair machinery, producing a stable provirus.(10,13) Because of these properties, IN is a key target for drug therapy.”
BackgroundCosnefroy, O., Tocco, A., Lesbats, P., Thierry, S., Calmels, C., Wiktorowicz, T., Reigadas, S., Kwon, Y., de Cian, A., Desfarges, S., et al. (2011) · Journal of Virology · doi:10.1128/jvi.05425-11 · Cited by 39 · see citing works
“It has been shown that the postintegration repair processes (action of FEN1 and polymerases) cannot occur in vitro when IN is bound to its integration product and may require the active disassembly of the IN complex (3, 43), as has been previously reported for other transposases (25).”
BackgroundThe 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 39 · see citing works
“multiple DNA repair pathways are able to repair a similar substrate in vitro [2].”
BackgroundInfluentialSelf-citationHIV-1 Integrase: From Biology to Chemotherapeutics
Loizidou, E. Z., Nicolaou, C. A., Nicolaides, A. V., & Kostrikis, L. G. (2007) · Current HIV Research · doi:10.2174/157016207781023965 · Cited by 35 · see citing works
“These gaps are likely repaired by the action of host cell DNA repair enzymes [2, 57, 310].”
BackgroundDNA-induced Polymerization of HIV-1 Integrase Analyzed with Fluorescence Fluctuation Spectroscopy
Vercammen, J., Maertens, G. N., Gérard, M., Clercq, E. D., Debyser, Z., & Engelborghs, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205842200 · Cited by 33 · see citing works
Poly(ADP-Ribose) Polymerase 1 Is Not Strictly Required for Infection of Murine Cells by Retroviruses
Siva, A., & Bushman, F. (2002) · Journal of Virology · doi:10.1128/jvi.76.23.11904-11910.2002 · Cited by 36 · see citing works
“Recent data support the idea that host DNA repair enzymes may be important for the final DNA repair activity (28).”
BackgroundSelf-citationGoing beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis
Elliott, J. L., & Kutluay, S. B. (2020) · Viruses · doi:10.3390/v12091005 · Cited by 46 · see citing works
“In an in vitro study using model DNA substrates that mimicked retroviral integration intermediates, the base-excision repair (BER) pathway enzymes DNA polymerase β, flap endonuclease 1 (FEN1), and ligase I were able to repair the gap and 5′ two-base overhangs [90].”
BackgroundDelelis, O., Petit, C., Leh, H., Mbemba, G., Mouscadet, J. F., & Sonigo, P. (2005) · Retrovirology · doi:10.1186/1742-4690-2-31 · Cited by 30 · see citing works
“Following these reactions, host cell enzymes likely repair the gap remaining between host and provirus DNA [17,18].”
BackgroundLee, D. J., & Robinson, W. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5835-5847.2004 · Cited by 34 · see citing works
“Finally, the resulting gaps in the DNA are repaired, a step likely mediated by host DNA double-stranded break repair enzymes (16, 17, 68).”
BackgroundApetroaei, M.-M., Velescu, B. Ș., Nedea, M. I., Dinu‐Pîrvu, C. E., Drăgănescu, D., Fâcă, A. I., Udeanu, D. I., & Arsene, A. L. (2024) · Biomedicines · doi:10.3390/biomedicines12040915 · Cited by 35 · see citing works
“Host DNA repair enzymes correct an inconsistency left by the integration process [49,50], and the result is a provirus, which is a firmly incorporated form of viral DNA.”
BackgroundNatural Polymorphisms of integrase Among HIV Type 1-Infected South African Patients
Fish, M. Q., Hewer, R., Wallis, C., Venter, W. D., Stevens, W., & Papathanasopoulos, M. (2010) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2009.0249 · Cited by 32 · see citing works
Correll, T. A., & Klibanov, O. M. (2008) · Pharmacotherapy · doi:10.1592/phco.28.1.90 · Cited by 32 · see citing works
Nucleoprotein complex intermediates in HIV-1 integration
Li, M., & Craigie, R. (2009) · Methods · doi:10.1016/j.ymeth.2009.02.001 · Cited by 31 · see citing works
In Search of Authentic Inhibitors of HIV-1 Integration
Debyser, Z., Cherepanov, P., Maele, B. V., de Clercq, E., & Witvrouw, M. (2002) · Antiviral Chemistry & Chemotherapy · doi:10.1177/095632020201300101 · Cited by 31 · see citing works
“This step is probably carried out by cellular DNA repair enzymes (Yoder & Bushman, 2000), although a possible role of RT and IN (Chow et al., 1992) has been proposed.”
BackgroundIdentification of HIV integration sites in infected host genomic DNA.
Ciuffi, A., & Barr, S. (2011) · Methods · doi:10.1016/j.ymeth.2010.04.004 · Cited by 31 · see citing works
Gao, K., Wong, S., & Bushman, F. (2004) · Journal of Virology · doi:10.1128/jvi.78.13.6715-6722.2004 · Cited by 29 · see citing works
“modeled with purified cellular DNA repair enzymes (51).”
Self-citationGupta, K., Curtis, J. E., Krueger, S., Hwang, Y., Cherepanov, P., Bushman, F., & Duyne, G. V. (2012) · Structure · doi:10.1016/j.str.2012.08.023 · Cited by 28 · see citing works
“…1918–19 et al., 2012; Desfarges et al., 2006), Ku (Zheng et al., 2011), and Rad18 (Mulder et al., 2002) have all been reported to interact with IN and may play a role in repairing the gaps in retroviral DNA integration intermediates to complete the creation of provirus (Yoder and Bushman, 2000).”
BackgroundSelf-citationResistance to novel drug classes
Marcelin, A., Ceccherini-Silberstein, F., Perno, C., & Cálvez, V. (2009) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0b013e328331d4b1 · Cited by 27 · see citing works
Solution Conformation and Dynamics of the HIV-1 Integrase Core Domain*
Fitzkee, N. C., Masse, J. E., Shen, Y., Davies, D., & Bax, A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.113407 · Cited by 26 · see citing works
Characterization of HIV-1 integrase N-terminal mutant viruses.
Lloyd, A. G., Ng, Y.-S., Muesing, M., Simon, V., & Mulder, L. C. (2007) · Virology · doi:10.1016/j.virol.2006.10.007 · Cited by 26 · see citing works
“In this regard, it has been demonstrated that an excess of retroviral IN inhibits the access of repair polymerases to DNA gap repair reactions in vitro (Yoder and Bushman, 2000).”
BackgroundGupta, P., Garg, P., & Roy, N. (2012) · Chemical Biology and Drug Design · doi:10.1111/j.1747-0285.2012.01326.x · Cited by 25
Wang, L.-D., Liu, C.-L., Chen, W.-Z., & Wang, C.-X. (2005) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2005.08.274 · Cited by 25 · see citing works
Structural Properties of HIV Integrase·Lens Epithelium-derived Growth Factor Oligomers
Gupta, K., Diamond, T. L., Hwang, Y. S., Bushman, F. D., & Duyne, G. D. V. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.114413 · Cited by 24 · see citing works
Self-citationStudamire, B., & Goff, S. P. (2008) · Retrovirology · doi:10.1186/1742-4690-5-48 · Cited by 78 · see citing works
“The C-terminus of Fen-1 interacts with the transcription coactivator p300, which acetylates Fen-1 [65], and has been implicated in retroviral integration [66,67].”
Desfarges, S., Filippo, J. S., Fournier, M., Calmels, C., Caumont-Sarcos, A., Litvak, S., Sung, P., & Parissi, V. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl843 · Cited by 24 · see citing works
“Full integration of a viral DNA in the presence of IN as the sole viral protein reported here indicates that the cellular DNA repair step is essentially performed by the nuclear machinery, as suggested by others (37, 38), without ruling out the possible involvement of others viral proteins in the PIC context favoring…”
BackgroundCraigie, R. (2002) · doi:10.1128/9781555817954.ch25 · Cited by 24 · see citing works
Zawahir, Z., & Neamati, N. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.07.022 · Cited by 23 · see citing works
- Authors
- Yoder, K. E., & Bushman, F. D.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2000-12
- Volume
- 74
- Issue
- 23
- Pages
- 11191-11200
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC113210
- OpenAlex
- W2062774485
- Cited by
- 209
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 10 · 2014: 8 · 2013: 9 · 2012: 8
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- James B. Pendleton Charitable Trust
- National Institutes of Health (5p01gm056553-05)
- National Institute of General Medical Sciences (GM 56553)
- National Institute of Allergy and Infectious Diseases (AI 34786, R01AI034786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- retroviral integration, integrase, reverse transcriptase, flap endonuclease, DNA ligase, DNA polymerase beta, DNA polymerase delta, PCNA, XRCC4, mobile DNA elements, transposon insertion
- MeSH terms
- DNA Ligase ATP, Base Sequence, DNA Repair, DNA-Binding Proteins, Molecular Sequence Data, DNA Ligases, Retroviridae, RNA-Directed DNA Polymerase, Virus Integration, Protein Serine-Threonine Kinases, Integrases, DNA-Activated Protein Kinase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
