Modulation of LINE-1 retrotransposition by a human SAMHD1 polymorphism

White, Tommy E.; Brandariz-Núñez, Alberto; Han, Kyudong; Sawyer, Sara L.; Kim, Baek; Díaz-Griffero, Felipe

doi:10.1016/j.virep.2016.06.001

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…In another study, it was found that SAMHD1 binds to ORF2p at the stage of the L1 RNP functional complex; moreover, the inhibitory activity of SAMHD1 against L1 is regulated by phosphorylation of threonine 592, the dephosphorylation of which correlates with the repression of L1 [121]. In addition to this site, another polymorphic site S33 phosphorylation was identified, which contributes to the inhibition of L1 [348]. As shown in a recent work, SAMHD1 is a nucleocytoplasmic shuttling protein and thus is possibly involved in the inhibition of L1 in the cytoplasm and nucleus, and the presence of SAMHD1 in the cytoplasm contributes to a decrease in ORF2p [349].…”

Section: Interferon-induced Factors Inhibiting the Formation Of L1 Rnpmentioning

confidence: 99%

Factors Regulating the Activity of LINE1 Retrotransposons

Protasova

Andreeva

Rogaev

2021

Genes

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LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes and defects in the genes involved in their repression. This review discusses the molecular genetic mechanisms of the retrotransposition and regulation of the activity of L1 elements. The contribution of various factors controlling the expression and distribution of L1 elements in the genome occurs at all stages of the retrotransposition. The regulation of L1 elements at the transcriptional, post-transcriptional and integration into the genome stages is described in detail. Finally, this review also focuses on the evolutionary aspects of L1 accumulation and their interplay with the host regulation system.

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Section: Interferon-induced Factors Inhibiting the Formation Of L1 Rnpmentioning

confidence: 99%

Factors Regulating the Activity of LINE1 Retrotransposons

Protasova

Andreeva

Rogaev

2021

Genes

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“…Surprisingly, phosphomimetic mutations of T592 abolish the antiretroviral activity, but do not affect dNTP hydrolysis in vitro or in cells, which raises questions about the exact relationship between dNTP depletion and the restriction of retroviral replication 23 , 25 , 27 . It is also unclear whether and how the dNTPase activity contributes to other, less well-understood biological functions of SAMHD1, such as its roles in the DNA double-strand break repair 35 , interferon signaling 36 – 38 , restriction of LINE-1 retroelements 39 – 41 , degradation of nascent DNA at stalled replication forks 42 , and posttranscriptional control of mRNAs in regulatory T cells 43 . Involvement of nucleic acids in these distinct cellular activities suggests that the interaction of SAMHD1 with nucleic acids 44 – 49 may contribute to its function.…”

Section: Introductionmentioning

confidence: 99%

Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

Bhattacharya

Persaud

et al. 2021

Nat Commun

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SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein—dephosphorylation of deoxynucleotide triphosphates (dNTPs)—implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3’ to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.

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“…Overall, these experiments suggested that AGS observed in individuals with TREX1 mutations is triggered by the inability of TREX1 protein to degrade reverse-transcribed DNA from endogenous retroelements that are left in the cell, triggers the innate immune response. Moreover, it has recently been shown that SAMHD1 is involved in the restriction of endogenous retroelements in cycling cells and that this regulation is controlled by T592 phosphorylation, suggesting that the absence of SAMHD1 allows accumulation/replication of retroelements, which could trigger AGS or autoimmune diseases (Goodier, 2016; Herrmann et al, 2018; White et al, 2016; Zhao et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

SAMHD1 deficient human monocytes autonomously trigger type I interferon

Martínez‐López

Martín-Fernández

Buta

et al. 2018

Molecular Immunology

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Germline mutations in the human SAMHD1 gene cause the development of Aicardi-Goutières Syndrome (AGS), with a dominant feature being increased systemic type I interferon(IFN) production. Here we tested the state of type I IFN induction and response to, in SAMHD1 knockout (KO) human monocytic cells. SAMHD1 KO cells exhibited spontaneous transcription and translation of IFN-β and subsequent interferon-stimulated genes (ISGs) as compared to parental wild-type cells. This elevation of IFN-β and ISGs was abrogated via inhibition of the TBK1-IRF3 pathway in the SAMHD1 KO cells. In agreement, we found that SAMHD1 KO cells present high levels of phosphorylated TBK1 when compared to control cells. Moreover, addition of blocking antibody against type I IFN also reversed elevation of ISGs. These experiments suggested that SAMHD1 KO cells are persistently auto-stimulating the TBK1-IRF3 pathway, leading to an enhanced production of type I IFN and subsequent self-induction of ISGs.

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Modulation of LINE-1 retrotransposition by a human SAMHD1 polymorphism

Cited by 10 publications

References 37 publications

Factors Regulating the Activity of LINE1 Retrotransposons

Factors Regulating the Activity of LINE1 Retrotransposons

Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

SAMHD1 deficient human monocytes autonomously trigger type I interferon

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