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Determination of L1 retrotransposition kinetics in cultured cells
Open accessAbstract
L1 retrotransposons are autonomous retroelements that are active in the human and mouse genomes. Previously, we developed a cultured cell assay that uses a neomycin phosphotransferase ( neo ) retrotransposition cassette to determine relative retrotransposition frequencies among various L1 elements. Here, we describe a new retrotransposition assay that uses an enhanced green fluorescent protein (EGFP) retrotransposition cassette to determine retrotransposition kinetics in cultured cells. We show that retrotransposition is not detected in cultured cells during the first 48 h post-transfection, but then proceeds at a continuous high rate for at least 16 days. We also determine the relative retrotransposition rates of two similar human L1 retrotransposons, L1(RP)and L1.3. L1(RP)retrotransposed in the EGFP assay at a rate of approximately 0.5% of transfected cells/day, approximately 3-fold higher than the rate measured for L1.3. We conclude that the new assay detects near real time retrotransposition in a single cell and is sufficiently sensitive to differentiate retrotransposition rates among similar L1 elements. The EGFP assay exhibits improved speed and accuracy compared to the previous assay when used to determine relative retrotransposition frequencies. Furthermore, the EGFP cassette has an expanded range of experimental applications.
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“The episomal L1-EGFP reporter plasmid and the L1 5′UTR-Luciferase reporter plasmid used in this study were both described previously25,50.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [25]
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Cites
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Cited by
Sorted by citations
Hot L1s account for the bulk of retrotransposition in the human population
Brouha, B., Schustak, J., Badge, R. M., Lutz-Prigge, S., Farley, A. H., Moran, J. V., & Kazazian, H. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0831042100 · Cited by 1,073
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Muotri, A. R., Chu, V. T., Marchetto, M. C. N., Deng, W., Moran, J. V., & Gage, F. H. (2005) · Nature · doi:10.1038/nature03663 · Cited by 942
L1 retrotransposition in human neural progenitor cells
Coufal, N. G., Garcia-Perez, J. L., Peng, G. E., Yeo, G. W., Mu, Y., Lovci, M. T., Morell, M., O’Shea, K. S., Moran, J. V., & Gage, F. H. (2009) · Nature · doi:10.1038/nature08248 · Cited by 814
Biology of Mammalian L1 Retrotransposons
Ostertag, E. M., & Kazazian, H. H. (2001) · Annual Review of Genetics · doi:10.1146/annurev.genet.35.102401.091032 · Cited by 782
Self-citationHuman L1 Retrotransposition: cis Preference versus trans Complementation
Wei, W., Gilbert, N., Ooi, S. L., Lawler, J. F., Ostertag, E. M., Kazazian, H. H., Boeke, J. D., & Moran, J. V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.4.1429-1439.2001 · Cited by 637
“Finally, we demonstrated that the retrotransposition of an allele of JM101/L1RP tagged with an enhanced green fluorescent protein retrotransposition indicator cassette (39) was not affected by the coexpression of representative RD-L1s harboring the mneoI reporter cassette (not shown).”
BackgroundSelf-citationRetrotransposons Revisited: The Restraint and Rehabilitation of Parasites
Goodier, J. L., & Kazazian, H. H. (2008) · Cell · doi:10.1016/j.cell.2008.09.022 · Cited by 659
“Cell culture assays available for both L1 and Alu retrotransposition (Moran et al., 1996; Ostertag et al., 2000; Dewannieux et al., 2003) and improving in vitro assays for L1 endonucleolytic cleavage, TPRT, and reverse transcription should move the field forward more rapidly (Cost et al., 2002;…”
L1 retrotransposition in neurons is modulated by MeCP2
Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., & Gage, F. H. (2010) · Nature · doi:10.1038/nature09544 · Cited by 626
LINE1 Derepression in aged wild-type and SIRT6-deficient mice drives inflammation
Simon, M., Van Meter, M., Ablaeva, J., Ke, Z., Gonzalez, R. S., Taguchi, T., De Cecco, M., Leonova, K. I., Kogan, V., Helfand, S. L., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.02.014 · Cited by 498
“In order to assess the efficacy of NRTIs in inhibiting L1 in the context of SIRT6 KO, we transfected WT and SIRT6 KO mouse embryonic fibroblasts with either human or mouse L1-enhanced green fluorescent protein (EGFP) reporter cassettes (Ostertag et al., 2000) to measure de novo retrotransposition events.”
MethodTransposable elements in cancer
Burns, K. H. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.35 · Cited by 572
An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons
Jacobs, F. M. J., Greenberg, D., Nguyen, N., Haeussler, M., Ewing, A. D., Katzman, S., Paten, B., Salama, S. R., & Haussler, D. (2014) · Nature · doi:10.1038/nature13760 · Cited by 506
Restricting retrotransposons: a review
Goodier, J. L. (2016) · Mobile DNA · doi:10.1186/s13100-016-0070-z · Cited by 436
“The original neomycin phosphotransferase gene reporter [84–86] was later joined by enhanced green fluorescent protein, blasticidin S-resistance, firefly luciferase, and secreting gaussia luciferase gene constructs [51, 87–89] (Fig.”
BackgroundVan Meter, M., Kashyap, M., Rezazadeh, S., Geneva, A. J., Morello, T. D., Seluanov, A., & Gorbunova, V. (2014) · Nature Communications · doi:10.1038/ncomms6011 · Cited by 456
“To examine whether SIRT6 plays a role in suppressing L1 retrotransposition, we used a L1-EGFP reporter cassette 25 (Supplementary Fig.”
NONCODING RNAS IN THE MAMMALIAN CENTRAL NERVOUS SYSTEM
Cao, X., Yeo, G., Muotri, A. R., Kuwabara, T., & Gage, F. H. (2006) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.29.051605.112839 · Cited by 379
“Full-length cDNA sequencing of human cDNA clones suggests that half the transcripts are noncoding (Ota et al. 2004).”
MethodInfluentialYang, N., & Kazazian, H. H. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1141 · Cited by 420
“For the retrotransposition assay, an L1 element under investigation is tagged in its 3′ UTR with an antisense enhanced GFP ( EGFP ) cassette, which is driven by a heterologous cytomegalovirus (CMV) promoter, disrupted by a γ-globin intron in the same orientation as L1 and followed by a thymidine kinase ( TK ) polyaden…”
MethodL1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicismPreprint
Kano, H., Godoy, I., Courtney, C., Vetter, M. R., Gerton, G. L., Ostertag, E. M., & Kazazian, H. H. (2009) · Genes & Development · doi:10.1101/gad.1803909 · Cited by 368
“2005) is similar to those described here, but contains the human L1RP element (another highly active human L1) followed by an EGFP (enhanced green fluorescent protein) retrotransposition cassette (Ostertag et al. 2000) and does not contain insulators.”
MethodSelf-citationSelective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators
Liu, N., Lee, C. H., Swigut, T., Grow, E. J., Gu, B., Bassik, M. C., & Wysocka, J. (2017) · Nature · doi:10.1038/nature25179 · Cited by 376
Thomas, C. A., Tejwani, L., Trujillo, C. A., Negraes, P. D., Herai, R. H., Mesci, P., Macia, A., Crow, Y. J., & Muotri, A. R. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.07.009 · Cited by 330
“This construct contains a full-length retrotransposition-competent L1 element (LRE3) tagged with a mEGFP1 retrotransposition indicator cassette (Ostertag et al., 2000) in a modified version of pCEP4 (Invitrogen) that lacks a CMV promoter and contains an mCherry cassette in place of the puromycin resistance marker.”
BackgroundMethodThe Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes
Richardson, S. R., Doucet, A. J., Kopera, H. C., Moldovan, J. B., Garcia-Perez, J. L., & Moran, J. V. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0061-2014 · Cited by 338
“The fi rst study to experimentally recapitulate LINE-1 retrotransposition in vivo used transgenic mice harboring an engineered human LINE-1 tagged with an EGFP retrotransposition indicator cassette (195).”
MethodAPOBEC3B and APOBEC3F Inhibit L1 Retrotransposition by a DNA Deamination-independent Mechanism
Stenglein, M. D., & Harris, R. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602367200 · Cited by 277
MOV10 RNA Helicase Is a Potent Inhibitor of Retrotransposition in Cells
Goodier, J. L., Cheung, L. E., & Kazazian, H. H. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002941 · Cited by 260
“2 retrotransposition reporter constructs have been described [28,34,49].”
BackgroundMethodInfluentialDifferential L1 regulation in pluripotent stem cells of humans and apes
Marchetto, M. C., Narvaiza, I., Denli, A. M., Benner, C. W., Lazzarini, T. A., Nathanson, J. L., Paquola, A. C. M., Desai, K. N., Herai, R. H., Weitzman, M. D., et al. (2013) · Nature · doi:10.1038/nature12686 · Cited by 241
The non-autonomous retrotransposon SVA is trans -mobilized by the human LINE-1 protein machinery
Raiz, J., Damert, A., Chira, S., Held, U., Jung‐Klawitter, S., Hamdorf, M., Löwer, J., Strätling, W. H., Löwer, R., & Schumann, G. G. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr863 · Cited by 235
“The percentage of green fluorescent cells was used to determine the transfection efficiency of each sample (2,29).”
BackgroundMethodCoufal, N. G., Garcia-Perez, J. L., Peng, G. E., Marchetto, M. C. N., Muotri, A. R., Mu, Y., Carson, C. T., Macia, A., Moran, J. V., & Gage, F. H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100273108 · Cited by 229
“L1RP–enhanced green fluorescent protein (EGFP) transgenic mice harbor a retrotransposition-competent human L1 driven by its native promoter (13, 24).”
BackgroundMethodResultInfluentialLINE-1 retrotransposition in human embryonic stem cells
Garcia-Perez, J. L., Marchetto, M. C., Muotri, A. R., Coufal, N. G., Gage, F. H., O’Shea, K. S., & Moran, J. V. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm105 · Cited by 235
“RP-hygro that contains the double missense mutation RR261- 262AA in ORF1p ( 38 ).”
BackgroundMethodInfluentialHuman LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells
Belgnaoui, S. M., Gosden, R. G., Semmes, O. J., & Haoudi, A. (2006) · Cancer Cell International · doi:10.1186/1475-2867-6-13 · Cited by 219
“To monitor EGFP-tagged RC-L1 expression and retrotransposition, we have used a retrotransposition assay that has previously been shown to efficiently detect and monitor L1 retrotransposition events in different cell lines [16-18].”
Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx283 · Cited by 196
Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS
Krug, L., Chatterjee, N., Borges-Monroy, R., Hearn, S., Liao, W.-W., Morrill, K., Prazak, L., Rozhkov, N., Theodorou, D., Hammell, M., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006635 · Cited by 201
“This strategy has been successfully used to report mammalian LINE element mobilization(77).”
MethodModulation of LINE-1 and Alu/SVA Retrotransposition by Aicardi-Goutières Syndrome-Related SAMHD1
Zhao, K., Du, J., Han, X., Goodier, J. L., Li, P., Zhou, X., Wei, W., Evans, S. L., Li, L., Zhang, W., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.019 · Cited by 194
“To determine whether LINE-1 is a potential target of SAMHD1, we evaluated the effect of SAMHD1 on LINE-1 retrotransposition using a well-established reporter system in HEK293T cells (Moran et al., 1996; Niewiadomska et al., 2007; Ostertag et al., 2000) (Figure S1A).”
dbRIP: A highly integrated database of retrotransposon insertion polymorphisms in humans
Wang, J., Song, L., Grover, D., Azrak, S., Batzer, M. A., & Liang, P. (2006) · Human Mutation · doi:10.1002/humu.20307 · Cited by 206
“…and SVA elements, a composite type of retrotransposon formed of SINE-R, VNTR, and Alu [Boeke, 1997; Boeke and Chapman, 1991; Deininger and Batzer, 2002; Dewannieux et al., 2003; Ostertag et al., 2000, 2002, 2003; Sassaman et al., 1997; Shen et al., 1994; Wang et al., 2005; Wang et al., 2006].”
Backgroundp53 genes function to restrain mobile elementsPreprint
Wylie, A., Jones, A. E., D’Brot, A., Lu, W.-J., Kurtz, P., Moran, J. V., Rakheja, D., Chen, K. S.-M., Hammer, R. E., Comerford, S. A., et al. (2015) · Genes & Development · doi:10.1101/gad.266098.115 · Cited by 204
“A key feature of this integration reporter is that EGFP is interrupted by an artificial intron oriented in the same transcriptional direction as L1 expression (Ostertag et al. 2000).”
L1 retrotransposition can occur early in human embryonic development
van den Hurk, J. A. J. M., Meij, I. C., del Carmen Seleme, M., Kano, H., Nikopoulos, K., Hoefsloot, L. H., Sistermans, E. A., de Wijs, I. J., Mukhopadhyay, A., Plomp, A. S., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm108 · Cited by 193
“L1CHM was tested in an established cultured cell assay that uses an enhanced green fluorescent protein (EGFP) marker to determine retrotransposition activity (1,26).”
MethodRetrotransposition of marked SVA elements by human L1s in cultured cells
Hancks, D. C., Goodier, J. L., Mandal, P. K., Cheung, L. E., & Kazazian, H. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr245 · Cited by 191
“As a positive control for trans-mobilization, JM111 EGFP Pur (76) and a driver L1 were also co-transfected.”
BackgroundMethodInfluentialYu, F. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.21.4493 · Cited by 195
“Retrotransposition was previously demonstrated to start 48 h post-transfection and to proceed at a continuous high rate for at least 16 days (31).”
BackgroundUnconventional translation of mammalian LINE-1 retrotransposonsPreprint
Alisch, R. S., Garcia-Perez, J. L., Muotri, A. R., Gage, F. H., & Moran, J. V. (2006) · Genes & Development · doi:10.1101/gad.1380406 · Cited by 186
“However, we cannot rule out a variation of termination/reinitiation mechanism that is employed by other types of viruses or artificial constructs that contain long upstream reading frame (Peabody and Berg 1986; Gowda et al. 1989; Horvath et al. 1990; Ahmadian et al. 2000; see below).”
MethodLINE-1 Evasion of Epigenetic Repression in Humans
Sanchez-Luque, F. J., Kempen, M.-J. H. C., Gerdes, P., Vargas-Landin, D. B., Richardson, S. R., Troskie, R.-L., Jesuadian, J. S., Cheetham, S. W., Carreira, P. E., Salvador-Palomeque, C., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.024 · Cited by 161
A mouse model of human L1 retrotransposition
Ostertag, E. M., DeBerardinis, R. J., Goodier, J. L., Zhang, Y., Yang, N., Gerton, G. L., & Kazazian, H. H. (2002) · Nature Genetics · doi:10.1038/ng1022 · Cited by 188
“We then cloned an antisense intron into EGFP to create a retrotransposition cassette similar to that used in our cell culture assa”
MethodSelf-citationL1 retrotransposition in nondividing and primary human somatic cells
Kubo, S., Seleme, M. D. C., Soifer, H. S., Garcia-Perez, J. L., Moran, J. V., Kazazian, H. H., & Kasahara, N. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601954103 · Cited by 180
LINE-1 Retrotransposition Requires the Nucleic Acid Chaperone Activity of the ORF1 Protein
Martin, S. L., Cruceanu, M., Branciforte, D., Li, P. W.-L., Kwok, S. C., Hodges, R. S., & Williams, M. C. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.03.003 · Cited by 178
Environmental influence on L1 retrotransposons in the adult hippocampus
Muotri, A. R., Zhao, C., Marchetto, M. C., & Gage, F. H. (2009) · Hippocampus · doi:10.1002/hipo.20564 · Cited by 175
“The potential founders were screened by PCR using primers as previously described (Ostertag et al., 2000).”
MethodEpigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells
Garcia-Perez, J. L., Morell, M. H., Scheys, J. O., Kulpa, D. A., Morell, S., Carter, C. C., Hammer, G. D., Collins, K. L., O’Shea, K. S., Menéndez, P. R., et al. (2010) · Nature · doi:10.1038/nature09209 · Cited by 186
The Role of Transposable Elements in Health and Diseases of the Central Nervous System
Reilly, M. T., Faulkner, G. J., Dubnau, J., Ponomarev, I., & Gage, F. H. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3369-13.2013 · Cited by 175
“…L1 activity was primarily supplied by (1) engineered L1 reporter assays, measuring mobilization of an EGFP tagged L1 (L1-EGFP) in vitro and in vivo (Ostertag et al., 2000; Muotri et al., 2005, 2009; Coufal et al., 2009), and (2) L1 copy number variation (CNV) assays based on TaqMan qPCR of genomic…”
BackgroundMethodInfluentialMapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition
Goodier, J. L., Cheung, L. E., & Kazazian, H. H. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt512 · Cited by 180
“Tagging ORF1 in this manner diminishes (to 30%) but maintains cell culture retrotransposition of L1RP in an EGFP-based reporter assay (29,45).”
BackgroundMethodAn important role for RUNX3 in human L1 transcription and retrotransposition
Yang, N. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg663 · Cited by 167
“To study the regulation of L1Hs retrotransposition, we used random mutagenesis to identify important sequences in L1RP, one of the most active known L1Hs (43,48).”
MethodA Comprehensive Analysis of Recently Integrated Human Ta L1 Elements
Myers, J. S., Vincent, B. J., Udall, H., Watkins, W. S., Morrish, T. A., Kilroy, G. E., Swergold, G. D., Henke, J., Henke, L., Moran, J. V., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/341718 · Cited by 158
“Differential mobilization of SINEs and LINEs has been elsewhere reported in rodent genomes (Kim and Deininger 1996; Ostertag et al. 2000).”
BackgroundEngineered LINE-1 retrotransposition in nondividing human neuronsPreprint
Macia, Á., Widmann, T. J., Heras, S. R., Ayllón, V., Sánchez, L., Benkaddour-Boumzaouad, M., Muñoz-López, M., Rubio, A., Amador‐Cubero, S., Blanco-Jimenez, E., et al. (2016) · Genome Research · doi:10.1101/gr.206805.116 · Cited by 166
“…it is likely that the immediate early cytomegalovirus ( CMV ) promoter used to drive EGFP ex- pressionfromtheretrotransposedreport-er in Ad-L1 (Ostertag et al. 2000; Kubo et al. 2006) fails to efficiently express EGFP in cultured mature neuronal cells, at least under our experimental…”
InfluentialCell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication
Ardeljan, D., Steranka, J. P., Liu, C., Li, Z., Taylor, M. S., Payer, L. M., Gorbounov, M., Sarnecki, J. S., Deshpande, V., Hruban, R. H., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0372-1 · Cited by 135
Autophagy supports genomic stability by degrading retrotransposon RNA
Guo, H., Chitiprolu, M., GAGNON, D. R., Meng, L., Perez‐Iratxeta, C., Lagace, D. C., & Gibbings, D. (2014) · Nature Communications · doi:10.1038/ncomms6276 · Cited by 154
Reprogramming somatic cells into iPS cells activates LINE-1 retroelement mobility
Wissing, S., Muñoz-López, M., Macia, Á., Yang, Z., Montaño, M., Collins, W., Garcia-Perez, J. L., Moran, J. V., & Greene, W. C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr455 · Cited by 150
“Fully spliced L1 reporter constructs in the genomic DNA were detected as described (13,52).”
BackgroundMethodInfluentialRetroviral insertional mutagenesis:Tagging cancer pathways
Mikkers, H. M. M., & Berns, A. J. M. (2003) · Advances in cancer research · doi:10.1016/s0065-230x(03)88304-5 · Cited by 143
The ORF1 Protein Encoded by LINE‐1: Structure and Function During L1 Retrotransposition
Martin, S. L. (2006) · BioMed Research International · doi:10.1155/jbb/2006/45621 · Cited by 142
“Hence, when it was finally possible to measure L1 retrotransposition activity using an autonomous retrotransposition assay [5, 33], it was unexpected to learn that mutations in ORF1 were at least as severe, if not more so, than those that abolish reverse transcriptase activity.”
Deleterious transposable elements and the extinction of asexuals
Arkhipova, I. R., & Meselson, M. S. (2004) · BioEssays · doi:10.1002/bies.20159 · Cited by 142
Gamma radiation increases endonuclease-dependent L1 retrotransposition in a cultured cell assay
Farkash, E. A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj522 · Cited by 141
The Zinc-Finger Antiviral Protein ZAP Inhibits LINE and Alu Retrotransposition
Moldovan, J. B., & Moran, J. V. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005121 · Cited by 147
“The 30-UTR contains themneoI retrotransposition indicator cassette [26].”
BackgroundMethodInfluentialIFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation
Hotter, D., Bosso, M., Jønsson, K. L., Krapp, C., Stürzel, C. M., Das, A. T., Littwitz-Salomon, E., Berkhout, B., Russ, A., Wittmann, S., et al. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.05.002 · Cited by 133
“LINE-1 retrotransposition assay—The retrotransposition-competent L1-GFP reporter plasmid (99 PUR L1RP EGFP) and the retrotransposition-defective negative control plasmid (99 PUR JM111 EGFP) have been described previously (Ostertag et al., 2000).”
MethodThe Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition
Goodier, J. L., Pereira, G., Cheung, L. E., Rose, R. J., & Kazazian, H. H. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005252 · Cited by 138
“In this assay, an enhanced green fluorescent protein (EGFP) reporter gene cassette, interrupted by a backwards intron and inserted in opposite transcriptional orientation into the 3' UTR of L1-RP (a highly active L1 [36]), is expressed only when the L1 transcript is spliced, reversetranscribed, its cDNA inserted in th…”
BackgroundMethodZhu, C., Gao, W., Zhao, K., Qin, X., Zhang, Y., Peng, X., Zhang, L., Dong, Y., Zhang, W., Li, P., et al. (2013) · Nature Communications · doi:10.1038/ncomms3722 · Cited by 127
Evidence consistent with human L1 retrotransposition in maternal meiosis I
Brouha, B., Meischl, C., Ostertag, E., de Boer, M., Zhang, Y., Neijens, H., Roos, D., & Kazazian, H. H. (2002) · The American Journal of Human Genetics · doi:10.1086/341722 · Cited by 122
Self-citationSAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation
Hu, S., Li, J., Xu, F., Mei, S., Le Duff, Y., Yin, L., Pang, X., Cen, S., Jin, Q., Liang, C., et al. (2015) · PLOS Genetics · doi:10.1371/journal.pgen.1005367 · Cited by 121
“The LINE-1 EGFP reporter construct was utilized to examine the effect of arsenite treatment on LINE-1 retrotransposition as described [74].”
MethodGarcia-Perez, J. L., Doucet, A. J., Bucheton, A., Moran, J. V., & Gilbert, N. (2007) · Genome Research · doi:10.1101/gr.5870107 · Cited by 121
“Seventy-two hours post-transfection, the HeLa cells in one set of 6-well tissue culture plates was trypsinized and subjected to flow cytometry (Ostertag et al. 2000; Wei et al. 2000).”
MethodActive retrotransposition by a synthetic L1 element in mice
An, W., Han, J. S., Wheelan, S. J., Davis, E. S., Coombes, C. E., Ye, P., Triplett, C., & Boeke, J. D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605300103 · Cited by 116
LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways
Zhao, K., Du, J., Peng, Y., Li, P., Wang, S., Wang, Y., Hou, J., Kang, J., Zheng, W., Hua, S., et al. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.02.007 · Cited by 106
p53 directly represses human LINE1 transposonsPreprint
Tiwari, B., Jones, A. E., Caillet, C. J., Das, S., Royer, S. K., & Abrams, J. (2020) · Genes & Development · doi:10.1101/gad.343186.120 · Cited by 120
“To determine whether retrotransposition rates are similarly affected, we stably transfected parental and p53 knockout A375 and U2OS cells with a synthetic L1 designated 99-gfp-LRE3 (Ostertag et al. 2000; Kopera et al. 2016).”
BackgroundMethodL1 Mosaicism in Mammals: Extent, Effects, and Evolution
Faulkner, G. J., & Garcia-Perez, J. L. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.07.004 · Cited by 118
Niewiadomska, A. M., Tian, C., Tan, L., Wang, T., Sarkis, P. T. N., & Yu, X.-F. (2007) · Journal of Virology · doi:10.1128/jvi.02800-06 · Cited by 107
“sense mutations in open reading frame 1 that abolishes retrotransposition ( 38 ).”
BackgroundWei, W., Morrish, T. A., Alisch, R. S., & Moran, J. V. (2000) · Analytical Biochemistry · doi:10.1006/abio.2000.4675 · Cited by 105
p53 responsive elements in human retrotransposons
Harris, C. R., DeWan, A. T., Zupnick, A., Normart, R., Gabriel, A., Prives, C. L., Levine, A. J., & Hoh, J. (2009) · Oncogene · doi:10.1038/onc.2009.246 · Cited by 110
“The plasmid 99PUR-RPSeGFP was a gift from H Kazazian (University of Pennsylvania) and has been described previously (Ostertag et al., 2000).”
MethodSeleme, M. D. C., Vetter, M. R., Cordaux, R., Bastone, L. A., Batzer, M. A., & Kazazian, H. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601324103 · Cited by 104
Characterization of L1 retrotransposition with high-throughput dual-luciferase assays
Xie, Y., Rosser, J. M., Thompson, T. L., Boeke, J. D., & An, W. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq1076 · Cited by 98
“The intron-disrupted Fluc cassette from pWA304 (or pWA303) was released as a BglII/EcoRV fragment, which was ligated either to a PmlI/BamHI digested CMVCAG-ORFeus plasmid to derive pWA346 (or pWA345), or to a NotI/BstZ17I fragment of 5-UTR-L1RP from pJCC5-RPS (19) and a NotI/BamHI fragment from a CMV-less version of p…”
BackgroundMethodInfluentialWissing, S., Montaño, M., Garcia-Perez, J. L., Moran, J. V., & Greene, W. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.251058 · Cited by 110
Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia
Gu, Z., Liu, Y., Zhang, Y., Cao, H., Lyu, J., Wang, X., Wylie, A., Newkirk, S. J., Jones, A. E., Lee, M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00829-8 · Cited by 111
Jones, R. B., Garrison, K. E., Wong, J. C., Duan, E. H., Nixon, D. F., & Ostrowski, M. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001547 · Cited by 99
“This system is described in detail elsewhere, and portrayed in Figure 1A [29].”
MethodL1 retrotransposons, cancer stem cells and oncogenesis
Carreira, P. E., Richardson, S. R., & Faulkner, G. J. (2013) · FEBS Journal · doi:10.1111/febs.12601 · Cited by 100
Mammalian LINE‐1 Retrotransposons and Related Elements
Moran, J. V., & Gilbert, N. (2007) · Wiley eBooks · doi:10.1128/9781555817954.ch35 · Cited by 103
L1 integration in a transgenic mouse modelPreprint
Babushok, D. V., Ostertag, E. M., Courtney, C., Choi, J. M., & Kazazian, H. H. (2005) · Genome Research · doi:10.1101/gr.4571606 · Cited by 99
“Mless was cloned into the pJCC5-L1LRE3 (Ostertag et al. 2000; Brouha et al. 2002) to create pBS-L1LRE3-mless.”
MethodSelf-citationSoifer, H. S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki223 · Cited by 98
Tracking an embryonic L1 retrotransposition event
Prak, E. T. L., Dodson, A. W., Farkash, E. A., & Kazazian, H. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0337627100 · Cited by 97
Mobile elements in the human genome: implications for disease
Sólyom, S., & Kazazian, H. H. (2012) · Genome Medicine · doi:10.1186/gm311 · Cited by 98
“One such system could be a retro transposition assay, where an L1 reporter construct has been designed so that translation of the reporter (drug-resis tance gene or enhanced green fluorescent protein) occurs only after L1 reverse transcription and insertion of its cDNA copy into the genome [88,89].”
BackgroundCell Divisions Are Required for L1 Retrotransposition
Shi, X., Seluanov, A., & Gorbunova, V. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01888-06 · Cited by 93
“To detect retrotransposition, we used a cassette containing EGFP-tagged L1 expressed under control of its endogenous promoter (28).”
BackgroundMethodInfluentialHarris, C. R., Normart, R., Yang, Q., Stevenson, E., Haffty, B. G., Ganesan, S., Cordon‐Cardo, C., Levine, A. J., & Tang, L. H. (2010) · Genes & Cancer · doi:10.1177/1947601909360812 · Cited by 93
“The plasmid 99PUR RPS eGFP (Ostertag et al.(50)) was a generous gift from the laboratory of H.”
G-quadruplex structures within the 3′ UTR of LINE-1 elements stimulate retrotransposition
Sahakyan, A. B., Murat, P., Mayer, C., & Balasubramanian, S. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3367 · Cited by 92
Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s
Warkocki, Z., Krawczyk, P. S., Adamska, D., Bijata, K., Garcia-Perez, J. L., & Dziembowski, A. (2018) · Cell · doi:10.1016/j.cell.2018.07.022 · Cited by 93
“We co-transfected HEK293T cells with an active human L1 reporter tagged with the megfpI cassette (Ostertag et al., 2000), together with plasmids for overexpression of wild-type (WT) TUT4, TUT7, TUT1, or TUT4 and TUT7 catalytically inactive mutants.”
InfluentialFrequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites
Tao, J., Wang, Q., Mendez‐Dorantes, C., Burns, K. H., & Chiarle, R. (2022) · Nature Communications · doi:10.1038/s41467-022-31322-3 · Cited by 91
Dissection of affinity captured LINE-1 macromolecular complexes
Taylor, M. S., Altukhov, I. A., Molloy, K. R., Mita, P., Jiang, H. L., Adney, E. M., Wudzinska, A. M., Badri, S., Ischenko, D. S., Eng, G. M., et al. (2018) · eLife · doi:10.7554/elife.30094 · Cited by 87
APOBEC3 proteins: major players in intracellular defence against LINE-1-mediated retrotransposition
Schumann, G. G. (2007) · Biochemical Society Transactions · doi:10.1042/bst0350637 · Cited by 83
Tan, L., Sarkis, P. T. N., Wang, T., Tian, C., & Yu, X. (2008) · The FASEB Journal · doi:10.1096/fj.07-088781 · Cited by 84
“1A) using a well-established cell culturebased LINE-1 retrotransposition assay (72, 75, 76).”
Horn, A. V., Jung‐Klawitter, S., Held, U., Berger, A., Vasudevan, A. A. J., Bock, A., Hofmann, H., Hanschmann, K.-M. O., Trösemeier, J., Flory, E., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt898 · Cited by 83
“The percentage of green fluorescent cells was used to determine the transfection efficiency of each sample (66,67), which reproducibly ranged from 64 to 70%.”
MethodLi, P., Du, J., Goodier, J. L., Hou, J., Kang, J., Kazazian, H. H., Zhao, K., & Yu, X.-F. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx178 · Cited by 91
“Fluorescent imaging indicated that fixation of cells with paraformaldehyde did not alter the localization of ORF1p or TREX1 or their co-localization (Supplementary Figure S10).”
MethodInfluentialSIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina
Vazquez, B. N., Thackray, J. K., Simonet, N. G., Chahar, S., Kane-Goldsmith, N., Newkirk, S. J., Lee, S., Xing, J., Verzi, M. P., An, W., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz519 · Cited by 79
“Third, the SV40 promoter in pMD3 was replaced with L1RP 5′UTR promoter by ligating the 5′UTR from pJCC5-RPS (73) as a EcoRV/NcoI fragment with EcoRV/NcoI digested pMD3, making pMD7.”
MethodL1 retrotransposition in the soma: a field jumping ahead
Faulkner, G. J., & Billon, V. (2018) · Mobile DNA · doi:10.1186/s13100-018-0128-1 · Cited by 85
Retrotransposon RNA expression and evidence for retrotransposition events in human oocytes
Georgiou, I. A., Noutsopoulos, D., Dimitriadou, E., Markopoulos, G. S., Apergi, A., Lazaros, L. A., Vaxevanoglou, T., Pantos, K., Syrrou, M., & Tzavaras, T. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp022 · Cited by 77
“Human oocytes cultured in medium were microinjected with 1–2 pg of engineered EGFP-tagged retrotransposons pNVL-3 /EGFP-INT for mouse VL30 (33) and a retrotransposition-competent pL1RP-EGFP(Puro) as well as an ORF2 mutant for human L1 (34,35).”
BackgroundMethodRetrotransposon-induced mosaicism in the neural genome
Bodea, G. O., McKelvey, E. G. Z., & Faulkner, G. J. (2018) · Open Biology · doi:10.1098/rsob.180074 · Cited by 80
LINE-1 retrotransposition in human neuroblastoma cells is affected by oxidative stress
Giorgi, G., Marcantonio, P., & Re, B. D. (2011) · Cell and Tissue Research · doi:10.1007/s00441-011-1289-0 · Cited by 79
Dai, L., Taylor, M. S., O’Donnell, K. A., & Boeke, J. D. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06785-11 · Cited by 74
“The pCEP-puro plasmid (61) was first modified by inserting a ligation-independent cloning (LIC) adaptor cassette into the SalI site, between the puro gene and the CMV promoter.”
MethodhnRNPL and nucleolin bind LINE-1 RNA and function as host factors to modulate retrotransposition
Peddigari, S., Li, P. W.-L., Rabe, J. L., & Martin, S. L. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1075 · Cited by 74
“Retrotransposition was measured using an autonomous retrotransposition assay where new insertions are detected by either quantification of eGFP expression using flow cytometry (31), or visualization of G418-resistant cells after fixation (9).”
MethodMobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells
MacLennan, M., García-Cañadas, M., Reichmann, J., Khazina, E., Wagner, G., Playfoot, C. J., Salvador‐Palomeque, C., Mann, A. R., Peressini, P., Sánchez, L., et al. (2017) · eLife · doi:10.7554/elife.26152 · Cited by 83
“Engineered L1 retrotransposition assays with an EGFP retrotransposition indicator cassette (Ostertag et al., 2000; Coufal et al., 2009) (Figure 5A) were used to measure the effect of Tex19.”
MethodSpadafora, C. (2008) · Human Reproduction · doi:10.1093/humrep/dem425 · Cited by 70
Turelli, P., Vianin, S., & Trono, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400334200 · Cited by 68
Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs
An, W., Dai, L., Niewiadomska, A. M., Yetil, A., O'Donnell, K. A., Han, J. S., & Boeke, J. D. (2011) · Mobile DNA · doi:10.1186/1759-8753-2-2 · Cited by 67
“[19] or neomycin (Neo-AI) [1] retrotransposition markers to monitor retrotransposition frequency.”
BackgroundMethodThe RNA Polymerase Dictates ORF1 Requirement and Timing of LINE and SINE Retrotransposition
Kroutter, E. N., Belancio, V. P., Wagstaff, B. J., & Roy‐Engel, A. M. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000458 · Cited by 69
“Similar results were previously observed using a green fluorescent protein (EGFP)tagged L1 element [45,50].”
ResultLINE-1 Retrotransposable Element DNA Accumulates in HIV-1-Infected Cells
Jones, R. B., Song, H., Xu, Y., Garrison, K. E., Buzdin, A. A., Anwar, N. M., Hunter, D. V., Mujib, S., Mihajlovic, V., Martin, E., et al. (2013) · Journal of Virology · doi:10.1128/jvi.02257-13 · Cited by 69
“The in vitro L1 retrotransposition assay is a modified version of a method which has been described elsewhere (6, 7, 63).”
BackgroundMethod
Metadata
- Authors
- Ostertag, E. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Ostertag, E. M.
- ORCID
- Ostertag, E. M.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-03-15
- Volume
- 28
- Issue
- 6
- Pages
- 1418-1423
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC111040
- OpenAlex
- W2150649207
- Cited by
- 291
- References
- 29
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 10 · 2023: 9 · 2022: 16 · 2021: 12 · 2020: 15 · 2019: 17 · 2018: 14 · 2017: 21 · 2016: 11 · 2015: 9 · 2014: 7 · 2013: 17 · 2012: 9
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- LINE-1 retrotransposons, cultured cells, transposable elements
- MeSH terms
- Cinnamates, Drug Resistance, False Positive Reactions, Globins, HeLa Cells, Humans, Hygromycin B, Introns, Kinetics, Luminescent Proteins, Microscopy, Fluorescence, Puromycin, Recombination, Genetic, RNA Splicing, Sensitivity and Specificity, Time Factors, Transfection, Mutagenesis, Insertional, Genes, Reporter, Retroelements, 3' Untranslated Regions, Green Fluorescent Proteins
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