Modulation of LINE-1 and Alu/SVA Retrotransposition by Aicardi-Goutières Syndrome-Related SAMHD1

Zhao, Ke; Du, Juan; Han, Xue; Goodier, John; Li, Peng; Zhou, Xiao Hong; Wei, Wei; Evans, Suzette M.; Li, Linzhang; Zhang, Wenyan; Cheung, Ling E.; Wang, Guanjun; Kazazian, Haig H.; Yu, Xiao Fang

doi:10.1016/j.celrep.2013.08.019

Cited by 182 publications

(229 citation statements)

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“…We have recently observed that the human SAMHD1 protein is a potent suppressor of LINE-1 activity 31 . To determine whether tetramer formation is also important for LINE-1 inhibition, we compared the functional activity of SAMHD1c 0 and SAMHD1c against LINE-1, using a well-established reporter system in HEK293T cells [32][33][34] .…”

Section: Articlementioning

confidence: 99%

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

et al. 2013

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SAMHD1 is a dGTP-activated deoxynucleoside triphosphate triphosphohydrolase (dNTPase) whose dNTPase activity has been linked to HIV/SIV restriction. The mechanism of its dGTPactivated dNTPase function remains unclear. Recent data also indicate that SAMHD1 regulates retrotransposition of LINE-1 elements. Here we report the 1.8-Å crystal structure of homotetrameric SAMHD1 in complex with the allosteric activator and substrate dGTP/dATP. The structure indicates the mechanism of dGTP-dependent tetramer formation, which requires the cooperation of three subunits and two dGTP/dATP molecules at each allosteric site. Allosteric dGTP binding induces conformational changes at the active site, allowing a more stable interaction with the substrate and explaining the dGTP-induced SAMHD1 dNTPase activity. Mutations of dGTP binding residues in the allosteric site affect tetramer formation, dNTPase activity and HIV-1 restriction. dGTP-triggered tetramer formation is also important for SAMHD1-mediated LINE-1 regulation. The structural and functional information provided here should facilitate future investigation of SAMHD1 function, including dNTPase activity, LINE-1 modulation and HIV-1 restriction.

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Section: Articlementioning

confidence: 99%

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

et al. 2013

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“…This mechanism of inhibition at least partially explains the decrease in LINE-1 ORF2 when SAMHD1 is overexpressed and drives sequestration of LNE-1 RNA in stress granules. 29,30 We also note that SAMHD1 specifically reduces the level of ORF2p but not ORF1p. 30 This is because the translation initiation of ORF2p is different from that of ORF1p.…”

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“…29,30 We also note that SAMHD1 specifically reduces the level of ORF2p but not ORF1p. 30 This is because the translation initiation of ORF2p is different from that of ORF1p. Since the inter-ORF spacer is dispensable for ORF2p translation, the translation of ORF2p most likely relies on the re-activation of ribosome that finishes the translation of ORF1p but has not dissociated from LINE-1 RNA.…”

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confidence: 99%

“…1). 30 Zhu et al also found that dGTP-triggered tetramer formation of SAMHD1 is important for dNTP depletion and SAMHD1-mediated inhibition of LINE-1 transposition. 35 Results from our group confirmed the restriction of LINE-1 by SAMHD1 and also suggested an alternative mechanism of action.…”

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confidence: 99%

“…In support of this scenario, results from our group and Yu lab have demonstrated that a viral restriction factor called SAMHD1 restricts LINE-1 retrotransposition. 29,30 As a deoxynucleotide triphosphate (dNTP) triphosphohydrolase, SAMHD1 inhibits HIV-1 infection in non-cycling cells by reducing dNTP level and thereby abrogating viral reverse transcription. 31,32 In contrast, in dividing cells, SAMHD1 is phosphorylated at amino acid T592 by cyclin A2/CDK1 and, as a result, loses its antiviral function.…”

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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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An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

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Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

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Modulation of LINE-1 and Alu/SVA Retrotransposition by Aicardi-Goutières Syndrome-Related SAMHD1

Cited by 182 publications

References 59 publications

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase

Stress out the LINEs

An update on post‐transcriptional regulation of retrotransposons

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