LINE-1 Elements in Structural Variation and Disease

Beck, Christine R.; García‐Pérez, José L.; Badge, Richard M.; Moran, John V.

doi:10.1146/annurev-genom-082509-141802

Cited by 489 publications

(542 citation statements)

References 261 publications

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“…L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 .…”

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confidence: 99%

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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VOLUME 22 NUMBER 10 OCTOBER 2015 nature structural & molecular biology a r t i c l e s microRNAs (miRs) are a class of small (~22-nt) genomically encoded molecules that inhibit translational initiation and stimulate decay of mRNA targets 1,2 . miRs are transcribed by RNA polymerase II and processed by the RNase III enzymes-Dicer and Drosha with its binding partner, DGCR8-to produce short double-stranded RNAs in the nucleus. One strand associates with the Argonaute (Ago) protein, thus forming the miR-mediated silencing complex (miRISC). miRs guide the pairing of miRISC, with imperfect complementarity, to sequences in target mRNAs, thus resulting in their subsequent destabilization and translational repression of the target 3 . The 'seed sequence' , at nucleotides 2-8, is a key determinant for miRISC-target recognition 4,5 . Recent data have shown that 35-40% of miR-binding sites are found in 3′ untranslated regions (UTRs), 40-50% in coding regions and <5% in 5′-UTR regions of mRNAs 6,7 . More than 60% of the human transcriptome has been predicted to be under miR regulation, thus making this post-transcriptional control pathway as important as protein pathways in the regulation of cell functions 2 . It is clear that miRs have essential roles in regulating diverse functions in normal and diseased cells 8,9 .L1 belongs to the most abundant class of autonomous transposable elements 10 . Human L1 contains two open reading frames, ORF1 and ORF2, which encode a protein with RNA-binding and nucleotide acid-chaperone activity (ORF1) 11 and a protein with endonuclease and reverse-transcriptase activities (ORF2) 12-15 , respectively. L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 . Mechanisms that operate at different levels in gene-expression hierarchies have been selected to control transposition-mediated mutagenesis and mitigate the potential negative effects of newly inserted elements. In germ cells, a specific small-RNA subtype (piwi-interacting RNAs (piRNAs)) efficiently counteracts L1 activity, but these RNAs are not expressed in nongerm cells 21,22 . Somatic cells attenuate element mobilization by DNA methylation of the L1 promoter 23 . Other methods of regulation are mediated by APOBEC proteins 24,25 , microprocessor interactions 26 and Ago-mediated RNA interference in mouse embryonic stem cells 27 . L1-promoter silencing is greatly attenuated, and L1 transcription is reactivated in hypomethylated cells, such as cancer cells and tumor-initiating cells, and is also reactivated during reprogramming [28][29][30] . Because miRs act as regulators of g...

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confidence: 99%

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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“…These autonomously replicating elements convert their RNA transcripts and those of other genetic elements, particularly SINEs, into genomic DNA (3). A generic L1 element is 6-7 kb and contains the following: a 5′ UTR; ORF1, which encodes the coiled-coil mediated trimeric nucleic acid chaperone protein ORF1p; ORF2, which encodes a DNA endonuclease and reverse-transcriptase ORF2p; and a 3′ UTR terminated in a polyA sequence (reviewed in refs.…”

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confidence: 99%

Phosphorylation of ORF1p is required for L1 retrotransposition

Cook

Jones

Furano

2015

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

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Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ∼100 million years and generated almost 40% of the human genome. The details of L1-host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host.L 1 (or LINE-1) activity over the last ∼100 million years of primate evolution has generated ∼40% of the human genome (1, 2); thus, succeeding families of L1 elements are the main drivers of genetic expansion. These autonomously replicating elements convert their RNA transcripts and those of other genetic elements, particularly SINEs, into genomic DNA (3). A generic L1 element is 6-7 kb and contains the following: a 5′ UTR; ORF1, which encodes the coiled-coil mediated trimeric nucleic acid chaperone protein ORF1p; ORF2, which encodes a DNA endonuclease and reverse-transcriptase ORF2p; and a 3′ UTR terminated in a polyA sequence (reviewed in refs. 3 and 4). ORF1p, ORF2p, and L1 RNA form ribonucleoprotein particles (RNPs) that are likely intermediates in L1 retrotransposition (5-8). The L1-encoded proteins ORF1p and ORF2p are essential in cell culture-based retrotransposition assays (9) and in vitro assays using RNPs from cells transfected with L1 retrotransposition vectors (7). Although the role of ORF1p in retrotransposition is not known, mutations that affect its nucleic acid binding and chaperone activities can inactivate L1 (7, 9, 10).L1 activity can damage DNA (11), can generate genetic diversity and rearrangements (12-16), and is activated in certain tumors (17-19) and other somatic cells (20), including neuronal cells (21-23). Despite being deleterious (2...

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“…ORF1 encodes a protein (ORF1p) with RNA binding and nucleic acid chaperone activity (6,7), whereas ORF2 encodes a protein (ORF2p) with endonuclease (8) and reverse transcriptase (9) activities. L1 retrotransposition occasionally can lead to disease and can impact human genome structural variation by various mechanisms (1,10,11). Heritable L1 insertions must occur in the germ line or during early embryonic development (11).…”

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confidence: 99%

“…L1 retrotransposition occasionally can lead to disease and can impact human genome structural variation by various mechanisms (1,10,11). Heritable L1 insertions must occur in the germ line or during early embryonic development (11). However, engineered human L1s can undergo somatic retrotransposition in the mammalian nervous system, and previous studies have demonstrated an increase in the DNA copy number of human-specific L1s in the brains of normal individuals compared with other somatic tissues (12,13).…”

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confidence: 99%

Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells

Coufal

García‐Pérez

Peng

et al. 2011

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

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Long interspersed element-1 (L1) retrotransposons compose ∼20% of the mammalian genome, and ongoing L1 retrotransposition events can impact genetic diversity by various mechanisms. Previous studies have demonstrated that endogenous L1 retrotransposition can occur in the germ line and during early embryonic development. In addition, recent data indicate that engineered human L1s can undergo somatic retrotransposition in human neural progenitor cells and that an increase in human-specific L1 DNA content can be detected in the brains of normal controls, as well as in Rett syndrome patients. Here, we demonstrate an increase in the retrotransposition efficiency of engineered human L1s in cells that lack or contain severely reduced levels of ataxia telangiectasia mutated, a serine/threonine kinase involved in DNA damage signaling and neurodegenerative disease. We demonstrate that the increase in L1 retrotransposition in ataxia telangiectasia mutateddeficient cells most likely occurs by conventional target-site primed reverse transcription and generate either longer, or perhaps more, L1 retrotransposition events per cell. Finally, we provide evidence suggesting an increase in human-specific L1 DNA copy number in postmortem brain tissue derived from ataxia telangiectasia patients compared with healthy controls. Together, these data suggest that cellular proteins involved in the DNA damage response may modulate L1 retrotransposition.

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LINE-1 Elements in Structural Variation and Disease

Cited by 489 publications

References 261 publications

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Phosphorylation of ORF1p is required for L1 retrotransposition

Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells

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