SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation

Hu, Siqi; Li, Jian; Xu, Feifei; Mei, Shan; Duff, Yann Le; Yin, Lijuan; Pang, Xiaowu; Cen, Shan; Jin, Qi; Liang, Chen; Guo, Fei

doi:10.1371/journal.pgen.1005367

Cited by 100 publications

(120 citation statements)

References 82 publications

(109 reference statements)

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“…Indeed, many restriction factors that were originally discovered because of their activity against viruses (including retroviruses) were subsequently shown to be potent restrictors of retrotransposons (transposable elements that mobilize via an RNA intermediate and reverse transcriptase activity) (Goodier et al, 2015;Hu et al, 2015;McLaughlin et al, 2014;Moldovan and Moran, 2015;Muckenfuss et al, 2006). However, one mechanism that is unique to transposon control stems from the fact that the transposons are resident within host genomes (among eukaryotic viruses, only retroviruses have this obligate requirement of host genome integration).…”

Section: The Scourge Of Transposable Elementsmentioning

confidence: 99%

Genetic conflicts: the usual suspects and beyond

McLaughlin

Malik

2017

Journal of Experimental Biology

130

121

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Selfishness is pervasive and manifests at all scales of biology, from societies, to individuals, to genetic elements within a genome. The relentless struggle to seek evolutionary advantages drives perpetual cycles of adaptation and counter-adaptation, commonly referred to as Red Queen interactions. In this review, we explore insights gleaned from molecular and genetic studies of such genetic conflicts, both extrinsic (between genomes) and intrinsic (within genomes or cells). We argue that many different characteristics of selfish genetic elements can be distilled into two types of advantages: an overreplication advantage (e.g. mobile genetic elements in genomes) and a transmission distortion advantage (e.g. meiotic drivers in populations). These two general categories may help classify disparate types of selfish genetic elements.

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Section: The Scourge Of Transposable Elementsmentioning

confidence: 99%

Genetic conflicts: the usual suspects and beyond

McLaughlin

Malik

2017

Journal of Experimental Biology

130

121

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“…Recently, Hu and colleagues provided evidences of a novel function of SAMHD1 in stimulating the formation of stress granules (SGs) and thus enhancing the sequestration of L1 RNP complexes in these granules (Hu et al 2015). This mechanism should impair nuclear import of L1 RNPs, thus affecting the retrotransposition process.…”

Section: Regulation Of Line-1 Expressionmentioning

confidence: 99%

Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases

et al. 2018

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Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/ APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within doublestranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.

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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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confidence: 62%

“…35 Results from our group confirmed the restriction of LINE-1 by SAMHD1 and also suggested an alternative mechanism of action. 29 The first key observation of our study is that SAMHD1 expression enhances the localization of LINE-1 RNP into cytoplasmic stress granules. In most cases, the stress-induced phosphorylation of the translation initiation factor eIF2a induces stress granule assembly by preventing or delaying translational initiation.…”

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confidence: 79%

“…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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confidence: 99%

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Stress out the LINEs

Liang

Guo

2015

Mobile Genetic Elements

Self Cite

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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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SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation

Cited by 100 publications

References 82 publications

Genetic conflicts: the usual suspects and beyond

Genetic conflicts: the usual suspects and beyond

Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases

Stress out the LINEs

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