Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons

Banuelos-Sanchez, Guillermo; Sánchez, Laura; Benitez‐Guijarro, Maria; Sanchez-Carnerero, Valentin; Salvador-Palomeque, Carmen; Tristán-Ramos, Pablo; Benkaddour-Boumzaouad, Meriem; Morell, Santiago; García-Puche, José L.; Heras, Sara R.; Franco-Montalbán, Francisco; Tamayo, Juan A.; García‐Pérez, José L.

doi:10.1016/j.chembiol.2019.04.010

Cited by 32 publications

(34 citation statements)

References 106 publications

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“…Endogenous L1 mRNA was quantified using N51 primers 85 . Transfected L1 mRNA was quantified using NEOjunct2 primers designed to exclusively amplify the spliced NEO cDNA 86 (in Supplementary Fig. 5a, b) or SV40 primers when the NEO cassette was absent ( Fig.…”

Section: Methodsmentioning

confidence: 99%

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

et al. 2020

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Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.

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Section: Methodsmentioning

confidence: 99%

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

et al. 2020

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“…The correlation between LINE-1 and disease as well as immunity was analyzed (Figure 2). The life cycle of LINE-1 provides a plethora of ways to target and inhibit LINE-1 expression (Banuelos-Sanchez et al, 2019). The inhibition of LINE-1 has become a treatment strategy for some diseases.…”

Section: Line-1 Inhibitionmentioning

confidence: 99%

New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

Zhang

2020

Front. Cell Dev. Biol.

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Long interspersed nuclear element-1 (LINE-1) retrotransposition is a major hallmark of cancer accompanied by global chromosomal instability, genomic instability, and genetic heterogeneity and has become one indicator for the occurrence, development, and poor prognosis of many diseases. LINE-1 also modulates the immune system and affects the immune microenvironment in a variety of ways. Aberrant expression of LINE-1 retrotransposon can provide strong stimuli for an innate immune response, activate the immune system, and induce autoimmunity and inflammation. Therefore, inhibition the activity of LINE-1 has become a potential treatment strategy for various diseases. In this review, we discussed the components and regulatory mechanisms involved with LINE-1, its correlations with disease and immunity, and multiple inhibitors of LINE-1, providing a new understanding of LINE-1.

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“…Treatment of early stage mouse embryos with either antisense L1 oligonucleotides, an antibody to RT, or the RT inhibitor nevirapine reportedly arrested preimplantation development at the 2-to 4-cell stage, perhaps by altering levels of cellular cDNA synthesized by RT [120,122]. (However, It should be noted, nonnucleoside reverse transciptase inhibitors like nevirapine, while they inhibit ERVs, were subsequently shown to not inhibit L1 cell culture retrotransposition [123][124][125]).…”

Section: A Possible Role For Misregulation Of Retrotransposon Expressmentioning

confidence: 99%

“…Administration of low doses of RT inhibitor to such patients could reduce the incidence of future retrotransposition and miscarriage. In cell culture experiments, L1 retrotransposition is strongly inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and recent studies have identified NRTIs that limit L1s and/or HERVs, including drugs widely used against HIV-1 infection [123][124][125]. Of interest, pilot clinical trials using NRTI inhibitors to reduce retrotransposon activity have begun for amyotrophic lateral sclerosis (Clinical-Trials.gov Identifiers NCT02437110, NCT02868580, [181]) and AGS (NCT02363452, NCT03304717).…”

Section: Testing the Hypothesismentioning

confidence: 99%

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

Lou

Goodier

Qiang

2020

Reprod Biol Endocrinol

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LINE1 retrotransposons are mobile DNA elements that copy and paste themselves into new sites in the genome. To ensure their evolutionary success, heritable new LINE-1 insertions accumulate in cells that can transmit genetic information to the next generation (i.e., germ cells and embryonic stem cells). It is our hypothesis that LINE1 retrotransposons, insertional mutagens that affect expression of genes, may be causal agents of early miscarriage in humans. The cell has evolved various defenses restricting retrotransposition-caused mutation, but these are occasionally relaxed in certain somatic cell types, including those of the early embryo. We predict that reduced suppression of L1s in germ cells or early-stage embryos may lead to excessive genome mutation by retrotransposon insertion, or to the induction of an inflammatory response or apoptosis due to increased expression of L1-derived nucleic acids and proteins, and so disrupt gene function important for embryogenesis. If correct, a novel threat to normal human development is revealed, and reverse transcriptase therapy could be one future strategy for controlling this cause of embryonic damage in patients with recurrent miscarriages.

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Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons

Abstract: Highlights d Characterization of 33 compounds has identified specific inhibitors of LINE-1s d GBS-149, FTC, and 3TC are non-toxic and mammalianspecific LINE-1 inhibitors d GBS-149 is a new and potent RTi of active human LINE-1s

Cited by 32 publications

References 106 publications

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

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