The MOV10 Helicase Inhibits LINE-1 Mobility

Li, Xiaoyü; Zhang, Jianyong; Jia, Rui; Cheng, Vicky; Xu, Xin; Qiao, Wentao; Guo, Fei; Liang, Chen; Cen, Shan

doi:10.1074/jbc.m113.465856

Cited by 94 publications

(130 citation statements)

References 60 publications

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“…MOV10 also restricts the retrotransposition of human LINE-1, Alu, SVA, and mouse IAP elements in cultured cells (372–374). The mechanism by which MOV10 inhibits LINE-1 retrotransposition requires elucidation.…”

Section: The Identification Of Host Factors That Regulate Line-1 Retrmentioning

confidence: 99%

The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes

et al. 2015

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Transposable elements have had a profound impact on the structure and function of mammalian genomes. The retrotransposon Long INterspersed Element-1 (LINE-1 or L1), by virtue of its replicative mobilization mechanism, comprises ∼17% of the human genome. Although the vast majority of human LINE-1 sequences are inactive molecular fossils, an estimated 80–100 copies per individual retain the ability to mobilize by a process termed retrotransposition. Indeed, LINE-1 is the only active, autonomous retrotransposon in humans and its retrotransposition continues to generate both intra-individual and inter-individual genetic diversity. Here, we briefly review the types of transposable elements that reside in mammalian genomes. We will focus our discussion on LINE-1 retrotransposons and the non-autonomous Short INterspersed Elements (SINEs) that rely on the proteins encoded by LINE-1 for their mobilization. We review cases where LINE-1-mediated retrotransposition events have resulted in genetic disease and discuss how the characterization of these mutagenic insertions led to the identification of retrotransposition-competent LINE-1s in the human and mouse genomes. We then discuss how the integration of molecular genetic, biochemical, and modern genomic technologies have yielded insight into the mechanism of LINE-1 retrotransposition, the impact of LINE-1-mediated retrotransposition events on mammalian genomes, and the host cellular mechanisms that protect the genome from unabated LINE-1-mediated retrotransposition events. Throughout this review, we highlight unanswered questions in LINE-1 biology that provide exciting opportunities for future research. Clearly, much has been learned about LINE-1 and SINE biology since the publication of Mobile DNA II thirteen years ago. Future studies should continue to yield exciting discoveries about how these retrotransposons contribute to genetic diversity in mammalian genomes.

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Section: The Identification Of Host Factors That Regulate Line-1 Retrmentioning

confidence: 99%

The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes

et al. 2015

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“…28 Our recent report shows that MOV10 also restricts the mobilization of long interspersed element 1 (LINE-1), which is an autonomous retrotransposon. 20 As shown in panels A and B of Figure 8, the siRNA with the XdT/dTX modification downregulated MOV10 protein expression by 62% in cell line HEK 293, whereas only 34 and 40% knockdown of MOV10 protein was observed in the presence of unmodified siRNA and dTX/XdT-modified siRNA, respectively. Again, chemical modification XdT/dTX improved siRNA potency to knock down gene expression.…”

Section: ■ Experimental Proceduresmentioning

confidence: 92%

“…Twelve days into selection when cell colonies were clearly visible, cell colonies were fixed with methanol at temperature for 10 min and stained with 0.5% crystal violet for 10 min. 20,25 ■ RESULTS Interactions between the PAZ Domain of Ago2 and the 3′-End of siRNA. The molecular modeling suite Sybyl was adopted to analyze the structure of the Ago2 protein PAZ domain (PDB entry 1SI2), and the results are shown in Figure 1.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Structure-Based Design of Novel Chemical Modification of the 3′-Overhang for Optimization of Short Interfering RNA Performance

Wang

et al. 2015

Biochemistry

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Short interfering RNAs (siRNAs) are broadly used to manipulate gene expression in mammalian cells. Although chemical modification is useful for increasing the potency of siRNAs in vivo, rational optimization of siRNA performance through chemical modification is still a challenge. In this work, we designed and synthesized a set of siRNAs containing modified two-nucleotide 3'-overhangs with the aim of strengthening the interaction between the 3'-end of the siRNA strand and the PAZ domain of Ago2. Their efficiency of binding to the PAZ domain was calculated using a computer modeling program, followed by measurement of RNA-Ago2 interaction in a surface plasmon resonance biochemical assay. The results suggest that increasing the level of binding of the 3'-end of the guiding strand with the PAZ domain, and/or reducing the level of binding of the sense strand through modifying the two-nucleotide 3'-overhangs, affects preferential strand selection and improves siRNA activity, while we cannot exclude the possibility that the modifications at the 3'-end of the sense strand may also affect the recognition of the 5'-end of the guiding strand by the MID domain. Taken together, our work presents a strategy for optimizing siRNA performance through asymmetric chemical modification of 3'-overhangs and also helps to develop the computer modeling method for rational siRNA design.

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“…Goodier et al first reported the localization of LINE-1 RNP components with stress granule markers. 38 [24][25][26] co-localize with LINE-1 RNP in stress granules or P-bodies (Fig. 1).…”

mentioning

confidence: 99%

“…[19][20][21][22][23] An RNA helicase MOV10 inhibits retrotransposition of LINE-1 by associating with LINE-1 RNP and diminishing LINE-1 RNA level. [24][25][26] A recent study by Goodier et al tested a panel of viral restriction factors and showed that many of them, including BST-2, ISG20, MAVS, Mx2 and ZAP, strongly reduce LINE-1 activity. 27 The anti-LINE-1 activity of ZAP was also reported by Moran group.…”

mentioning

confidence: 99%

Stress out the LINEs

Liang

Guo

2015

Mobile Genetic Elements

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Occupying 17% of human genome, the mobile long interspersed element 1 (LINE-1 or L1) continues to modulate the landscape of our genome by inserting into new loci and, as a result, causing sporadic diseases. It is not surprising that human cells have evolved a battery of mechanisms to control and limit the activity of LINE-1. Our recent study unravels such a mechanism that is imposed by the stress granule pathway. This mechanism functions by sequestering the LINE-1 RNA-protein complex within the cytoplasmic stress granules and thus inhibiting the nuclear import of LINE-1 RNA and its subsequent reverse transcription and integration into cellular DNA. Conditions that promote stress granule formation, such as expression of the SAMHD1 protein, further reduce LINE-1 retrotransposition.KEYWORDS host restriction; LINE-1; SAMHD1; stress granule; retrotransposition Approximately 45% of human genome has been derived from transposable elements. 1 These include DNA transposons, long terminal repeat (LTR) retrotransposons (also called endogenous retroviruses), and non-LTR retrotransposons. Long interspersed element 1 (LINE-1) belongs to non-LTR retrotransposons and comprises »17% of human genome. 1 Compared to the other transposons that have mostly become inactive, approximately 100 copies of LINE-1 are still active. 2 Retrotransposition of these LINE-1s is associated with nearly 100 human diseases. 3 LINE-1 encodes two proteins called ORF1 and ORF2. ORF1 is an RNA-binding protein and associates with LINE-1 RNA. [4][5][6][7] ORF2 is an enzyme that has endonuclease and reverse transcriptase activities. 8,9 ORF1, ORF2 and LINE-1 RNA together form an RNP complex that needs to enter the nucleus where LINE-1 RNA is reverse transcribed and integrated into cellular DNA. [10][11][12] Humans have survived LINE-1 invasion and amplification over millions of years thanks to the evolution of a battery of mechanisms that control LINE-1 activity. Some of these mechanisms begin to be unraveled as a result of intensive research in the past couple of decades. One such mechanism is suppression of LINE-1 transcription by methylating LINE-1 DNA. [13][14][15] In support of this mechanism, knockdown or knockout genes that are involved in DNA methylation leads to increase in the activities of LINE-1 and other transposons. 13 In the course of embryonic development there are a couple of waves of DNA demythlyation. DNA demethylation inevitably activates LINE-1 RNA expression. 16 To control retrotransposition of LINE-1 and other transposable elements, primordial germ cells (PGCs) are equipped with the piRNA machinery to inactivate LINE-1 so as to protect the integrity of genome DNA in germ cells. 17,18 Recent studies have revealed that cells have a rich layer of mechanisms that check LINE-1 activity at the post-transcription stage. Many of these mechanisms involve cellular factors that have been shown to restrict viral infections. One example is the APOBEC family of proteins that are cytidine deaminase and inactivate viral or LINE-1 DNA by intro...

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The MOV10 Helicase Inhibits LINE-1 Mobility

Cited by 94 publications

References 60 publications

The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes

The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes

Structure-Based Design of Novel Chemical Modification of the 3′-Overhang for Optimization of Short Interfering RNA Performance

Stress out the LINEs

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