L1 mobile element expression causes multiple types of toxicity

Wallace, Nicholas A.; Belancio, Victoria P.; Deininger, Prescott L.

doi:10.1016/j.gene.2008.04.013

Cited by 126 publications

(151 citation statements)

References 50 publications

(76 reference statements)

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“…However, we cannot exclude that ATM deficiency allows cells to accommodate more L1 retrotransposition events per cell. Finally, although we did not observe major changes in the cell cycle, growth, proliferation, or survival rates between ATM-proficient and ATMdeficient cells, it is formally possible that ATM deficiency could render cells more tolerant to L1-induced toxicity (29). Clearly, further experiments are required to determine why ATM deficiency results in higher levels of retrotransposition.…”

Section: Discussionmentioning

confidence: 61%

“…S7D). L1 expression has been reported to induce cellular toxicity (29). Thus, ATM-deficient cells may have an increased tolerance for L1-induced toxicity, allowing for increased survival of cells containing L1 events.…”

Section: Resultsmentioning

confidence: 99%

“…This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, "Telomerase and Retrotransposons: Reverse Transcriptases That Shaped Genomes," held September [29][30] 2010, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and audio files of most presentations are available on the NAS Web site at www.nasonline.…”

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confidence: 99%

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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.

212

179

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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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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

212

179

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“…At the protein level, overexpression of L1 ORF2 protein (ORF2p) is cytotoxic to cultured cells (60)(61)(62). In cultured cells, the ORF2p's endonuclease activity generates DNA double-strand breaks (DSBs) (62) but its reverse-transcriptase domain also contributes to cytotoxicity (60,63). Given the remarkable upregulation of ORF1p in piRNA pathway-deficient spermatocytes, ORF2p overexpression is expected.…”

Section: Discussionmentioning

confidence: 99%

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

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

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The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1 −/− testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1 −/− germ cells compared with the wildtype. Analysis of adult Mov10l1 −/− germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1 −/− phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense.LINE-1 reporter transgene | meiotic arrest | PIWI-interacting RNA | retrotransposition | spermatogenesis T he bulk of mammalian genomes are made up of transposable elements, the majority of which are retrotransposons (1). Retrotransposons are classified into long-interspersed elements (LINEs), short-interspersed elements (SINEs), and LTR retrotransposons, which collectively account for 43% and 37% of the human and mouse genomes, respectively (2). Retrotransposons amplify in the genome through an RNA intermediate, a process termed retrotransposition. LINEs are autonomous elements. An intact, full-length LINE-1 (L1) encodes two ORFs (i.e., ORF1 and ORF2); both are required for L1 mobilization (3). SINEs are nonautonomous elements and rely on L1's proteins for propagation in the genome (4). LTR retrotransposons are autonomous but appear to be inactivated in the human genome (5). Retrotransposition endangers the integrity of both somatic and germline genomes through insertional mutagenesis. In somatic tissues, both elevated L1 expression and retrotransposition have been strongly associated with many types of human cancers (6, 7). In a few cases, specific retrotransposition events (i.e., insertions) have been determined to drive t...

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“…A variety of mutant phenotypes caused by TE-induced insertions and rearrangements have also been documented in mouse, and include tumors, infertility and developmental pathologies (Bannert and Kurth, 2004). Independently of their activity, TE toxicity can occur in a retrotransposition-independent manner; overexpression of the L1 ORF2 protein single-handedly induces double-strand breaks and promotes apoptotic and senescence-like responses in cellular assays (Wallace et al, 2008). Finally, relaxation of TE silencing is a typical hallmark of cancerous and aging cells, in which it usually underlies a loss of genome-wide DNA methylation (Barbot et al, 2002;Schulz et al, 2006;Howard et al, 2008).…”

Section: Good Tes Bad Tesmentioning

confidence: 99%

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

2010

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Retrotransposable elements comprise around 50% of the mammalian genome. Their activity represents a constant threat to the host and has prompted the development of adaptive control mechanisms to protect genome architecture and function. To ensure their propagation, retrotransposons have to mobilize in cells destined for the next generation. Accordingly, these elements are particularly well suited to transcriptional networks associated with pluripotent and germinal states in mammals. The relaxation of epigenetic control that occurs in the early developing germline constitutes a dangerous window in which retrotransposons can escape from host restraint and massively expand. What could be observed as risky behavior may turn out to be an insidious strategy developed by germ cells to sense retrotransposons and hold them back in check. Herein, we review recent insights that have provided a detailed picture of the defense mechanisms that concur toward retrotransposon silencing in mammalian genomes, and in particular in the germline. In this lineage, retrotransposons are hit at multiple stages of their life cycle, through transcriptional repression, RNA degradation and translational control. An organized cross-talk between PIWIinteracting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories provides this potent and multilayered response to retrotransposon unleashing in early germ cells.

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L1 mobile element expression causes multiple types of toxicity

Cited by 126 publications

References 50 publications

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

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

Intact piRNA pathway prevents L1 mobilization in male meiosis

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

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