A New Family of Chimeric Retrotranscripts Formed by a Full Copy of U6 Small Nuclear RNA Fused to the 3′ Terminus of L1

Buzdin, Anton; Ustyugova, Svetlana V.; Gogvadze, Elena; Виноградова, Т. В.; Lebedev, Yuri B.; Свердлов, Е. Д.

doi:10.1006/geno.2002.6843

Cited by 100 publications

(128 citation statements)

References 14 publications

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“…Eighty-four out of 190 U6 pseudogenes observed in the human genome were associated with LINE elements, and 62 were not associated with any known repeats. Buzdin et al (2002) also observed that many of the U6 pseudogenes they identified were associated with LINEs. We found that 35 of the remaining U6 pseudogenes were associated with SINEs and nine were associated with retroviral LTRs.…”

Section: U6 Snrna Is Reverse-transcribed In Rsv Virionsmentioning

confidence: 84%

“…Buzdin and coworkers (2002) carried out a similar genomic analysis, restricted to full-length sequences, and identified 161 U6 snRNA pseudogenes in the human genome. Fifty-six of these integrants were adjacent to and in the same transcriptional orientation as a 3Ј fragment of the L1 LINE, suggesting that they were created by 3Ј transduction of U6 during L1 reverse transcription (Buzdin et al 2002). It was recently shown that L1 reverse transcription can transduce many other sequences (Buzdin et al 2003).…”

Section: Discussionmentioning

confidence: 99%

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Packaging and reverse transcription of snRNAs by retroviruses may generate pseudogenes

Giles¹,

Caputi²,

Beemon³

2004

RNA

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Retroviruses specifically package two copies of their RNA genome in each viral particle, along with some small cellular RNAs, including tRNAs and 7S L RNA. We show here that Rous sarcoma virus (RSV) also packages U6 snRNA at approximately one copy per virion. In addition, trace amounts of U1 and U2 snRNAs were detected in purified virus by Northern blotting. U6 snRNA comigrated with the RSV 70S genomic RNA dimer on sucrose gradients. We observed reverse transcription of U6 snRNA in an endogenous reaction in which RSV particles were the source of both reverse transcriptase and RNA substrates. This finding led us to examine mammalian genomic sequences for the presence of snRNA pseudogenes. A survey of the human, mouse, and rat genomes revealed a high number of spliceosomal snRNA pseudogenes. U6 pseudogenes were the most abundant, with approximately 200 copies in each genome. In the human genome, 67% of U6 snRNA pseudogenes, and a significant number of the other snRNA pseudogenes, were associated with LINE, SINE, or retroviral LTR repeat sequences. We propose that the packaging of snRNAs in retroviral particles leads to their reverse transcription in an infected cell and the integration of snRNA/viral recombinants into the host genome.

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Section: U6 Snrna Is Reverse-transcribed In Rsv Virionsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Packaging and reverse transcription of snRNAs by retroviruses may generate pseudogenes

Giles¹,

Caputi²,

Beemon³

2004

RNA

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“…RT template jumping was proposed to facilitate attachment of the 5Ј end of R2 to the host DNA during integration (George et al 1996;Burke et al 1999;Eickbush et al 2000;Bibillo and Eickbush 2002b), and our data suggest that template jumping may also be a feature of L1 retrotransposition. A similar mechanism was postulated to create chimeric L1 insertions (e.g., U6-L1) (Hayward et al 1997;Buzdin et al 2002Buzdin et al , 2003Gilbert et al 2005).…”

Section: L1 Rt Template Jumping Creates Extra 5ј Nucleotides and 5ј-ementioning

confidence: 99%

L1 integration in a transgenic mouse model

et al. 2005

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To study integration of the human LINE-1 retrotransposon (L1) in vivo, we developed a transgenic mouse model of L1 retrotransposition that displays de novo somatic L1 insertions at a high frequency, occasionally several insertions per mouse. We mapped 3Ј integration sites of 51 insertions by Thermal Asymmetric Interlaced PCR (TAIL-PCR). Analysis of integration locations revealed a broad genomic distribution with a modest preference for intergenic regions. We characterized the complete structures of 33 de novo retrotransposition events. Our results highlight the large number of highly truncated L1s, as over 52% (27/51) of total integrants were <1/3 the length of a full-length element. New integrants carry all structural characteristics typical of genomic L1s, including a number with inversions, deletions, and 5Ј-end microhomologies to the target DNA sequence. Notably, at least 13% (7/51) of all insertions contain a short stretch of extra nucleotides at their 5Ј end, which we postulate result from template-jumping by the L1-encoded reverse transcriptase. We propose a unified model of L1 integration that explains all of the characteristic features of L1 retrotransposition, such as 5Ј truncations, inversions, extra nucleotide additions, and 5Ј boundary and inversion point microhomologies.[Supplemental material is available online at www.genome.org.]The long interspersed nucleotide element-1 (L1) retrotransposon enjoyed tremendous evolutionary success in colonizing eukaryotic genomes (Kazazian Jr. 2004); its roughly 500,000 copies comprise ∼17% of human DNA (Lander et al. 2001). The full-length 6-kb L1 encodes a 5Ј UTR containing an internal promoter, two proteins-ORF1, a nucleic acid-binding protein with chaperone activity (Hohjoh andSinger 1996, 1997;Martin and Bushman 2001), and ORF2, a protein with endonuclease (EN) and reverse transcriptase (RT) activities (Mathias et al. 1991;Feng et al. 1996), and a 3Ј UTR ending with a poly(A) tail (Fig. 1A). Both ORF1 and ORF2 proteins are required for retrotransposition . Once transcribed and translated, L1 RNA is copied into the genome by target-primed reverse transcription (TPRT) (Luan et al. 1993;Cost et al. 2002). During TPRT, one strand of host DNA is cleaved by the EN to expose a free 3Ј-hydroxyl, which is then used by the RT as a primer in reverse transcription, copying the L1 RNA template directly into the host genome. To complete integration, the second strand of host DNA must be cleaved, RNA removed, the newly synthesized strand copied, and breaks resolved. The mechanism by which these later steps are accomplished is only beginning to be understood, with recent biochemical data from a related non-LTR retrotransposon R2 of the silkmoth, Bombyx mori, suggesting that a second R2 protein is involved in cleavage, RNA displacement, and synthesis of the second strand (Bibillo and Eickbush 2002a; Christensen and Eickbush 2005).Following essentially random integration, endogenous L1s are thought to be lost over time due to strong negative selection leading to their uneven ...

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“…23). ORF1p and/or ORF2p also can act in trans to mobilize short interspersed elements [e.g., Alu (24) and SINE-VNTR-Alu (25) elements], certain noncoding RNAs [e.g., U6 snRNA and small nucleolar RNAs (24,(26)(27)(28)(29)], and some cellular mRNAs, which leads to the formation of processed pseudogenes (30)(31)(32). In total, these trans retrotransposition events account for at least an additional 10% of human DNA (1).…”

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confidence: 99%

Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase

Kopera¹,

Moldovan²,

Morrish³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Long interspersed element-1 (LINE-1 or L1) retrotransposons encode two proteins (ORF1p and ORF2p) that contain activities required for conventional retrotransposition by a mechanism termed target-site primed reverse transcription. Previous experiments in XRCC4 or DNA protein kinase catalytic subunit-deficient CHO cell lines, which are defective for the nonhomologous endjoining DNA repair pathway, revealed an alternative endonuclease-independent (ENi) pathway for L1 retrotransposition. Interestingly, some ENi retrotransposition events in DNA protein kinase catalytic subunit-deficient cells are targeted to dysfunctional telomeres. Here we used an in vitro assay to detect L1 reverse transcriptase activity to demonstrate that wild-type or endonuclease-defective L1 ribonucleoprotein particles can use oligonucleotide adapters that mimic telomeric ends as primers to initiate the reverse transcription of L1 mRNA. Importantly, these ribonucleoprotein particles also contain a nuclease activity that can process the oligonucleotide adapters before the initiation of reverse transcription. Finally, we demonstrate that ORF1p is not strictly required for ENi retrotransposition at dysfunctional telomeres. Thus, these data further highlight similarities between the mechanism of ENi L1 retrotransposition and telomerase.L ong interspersed element-1 sequences (LINE-1s or L1s) are abundant non-long terminal repeat (non-LTR) retrotransposons that constitute approximately one-sixth (i.e., ≈17%) of human nuclear DNA (1). An estimated 80-100 full-length, retrotransposition competent L1s (RC-L1s) are present in a typical diploid human genome, and a small number, termed "hot L1s" exhibit high retrotransposition efficiencies in cultured human cells (2). Human RC-L1s are ≈6 kb (3, 4) and encode two proteins (ORF1p and ORF2p) required for retrotransposition (5). ORF1p is a 40-kDa protein (6) with RNA binding (7-12) and nucleic acid chaperone activities (13-15). ORF2p is a 150-kDa protein (16, 17) with endonuclease (EN) (18,19) and reverse transcriptase (RT) (20, 21) activities.The mobilization of RC-L1s can be mutagenic (22); germ line and, less often, somatic L1 insertions have led to ≈65 sporadic cases of disease in humans (reviewed in ref. 23). ORF1p and/or ORF2p also can act in trans to mobilize short interspersed elements [e.g., Alu (24) and SINE-VNTR-Alu (25) elements], certain noncoding RNAs [e.g., U6 snRNA and small nucleolar RNAs (24, 26-29)], and some cellular mRNAs, which leads to the formation of processed pseudogenes (30-32). In total, these trans retrotransposition events account for at least an additional 10% of human DNA (1). Moreover, several recent studies have further demonstrated that L1-mediated retrotransposition events are responsible for a significant proportion of interindividual genetic variation in the human population (33-39) and may cause intraindividual variation in the mammalian nervous system (40, 41). L1 retrotransposition likely occurs by a mechanism termed target-site primed reverse transcription (TPRT) (42)...

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A New Family of Chimeric Retrotranscripts Formed by a Full Copy of U6 Small Nuclear RNA Fused to the 3′ Terminus of L1

Cited by 100 publications

References 14 publications

Packaging and reverse transcription of snRNAs by retroviruses may generate pseudogenes

Packaging and reverse transcription of snRNAs by retroviruses may generate pseudogenes

L1 integration in a transgenic mouse model

Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase

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