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• W2967837582 abstract "In this issue of Cell Chemical Biology, Banuelos-Sanchez et al., 2019Banuelos-Sanchez G. Sanchez L. Benitez-Guijarro M. Sanchez-Carnerero V. Salvador-Palomeque C. Tristan-Ramos P. Benkaddour-Boumzaouad M. Morell S. Garcia-Puche J.L. Heras S.R. et al.Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.Cell Chem. Biol. 2019; 26 (this issue): 1095-1109Abstract Full Text Full Text PDF Scopus (19) Google Scholar present a comprehensive analysis of selective non-toxic inhibitors of reverse transcriptases encoded by endogenous retrotransposons. This work offers tools for the study of these retroelements, whose activity has been linked to cancer, neurological disorders, autoimmunity, and genomic instability. In this issue of Cell Chemical Biology, Banuelos-Sanchez et al., 2019Banuelos-Sanchez G. Sanchez L. Benitez-Guijarro M. Sanchez-Carnerero V. Salvador-Palomeque C. Tristan-Ramos P. Benkaddour-Boumzaouad M. Morell S. Garcia-Puche J.L. Heras S.R. et al.Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.Cell Chem. Biol. 2019; 26 (this issue): 1095-1109Abstract Full Text Full Text PDF Scopus (19) Google Scholar present a comprehensive analysis of selective non-toxic inhibitors of reverse transcriptases encoded by endogenous retrotransposons. This work offers tools for the study of these retroelements, whose activity has been linked to cancer, neurological disorders, autoimmunity, and genomic instability. The central dogma of molecular biology, that information flows from DNA to protein through an RNA intermediate, was upended with the discovery in 1970 of retroviral reverse transcriptase (RT) by the laboratories of David Baltimore at MIT and Howard Temin at the University of Wisconsin. Once a retrovirus enters a cell, its RNA genome is copied into double-stranded DNA by viral-encoded RT. RT hence became an early target for HIV treatment; following the clinical approval over 30 years ago of zidovudine (AZT), a host of other RT inhibitor (RTi) drugs were developed. These inhibitors fall into two subclasses: nucleos(t)ide reverse-transcriptase inhibitors [N(t)RTIs] and non-nucleoside reverse-transcriptase inhibitors (NNRTIs). NRTI nucleoside analogs lack a 3′-hydroxyl group and cause chain elongation termination when incorporated into reverse transcribing viral DNA. NNRTIs are not incorporated into DNA, but instead bind noncompetitively in a hydrophobic pocket proximal to the catalytic site of RT, causing a conformational change and preventing the enzyme from catalyzing DNA polymerization. Infections of reverse-transcribing RNA and DNA viruses are not the only source of RNA-dependent DNA polymerases in human cells. Three endogenous RTs exist, including telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase that synthesizes de novo telomere repeats and maintains the integrity of chromosome ends, and those encoded by human endogenous retroviruses (HERVs) and long interspersed element-1 (LINE-1 or L1) retrotransposons (Figure 1). Members of the LTR (long terminal repeat) class of retroelements, ERVs are remnants of past retroviral infections that lost their ability to infect new cells but increased in number through time to now comprise 8% of our genome. In humans, probably only the HERV-K(HML-2) group encodes functional RT from a small number of source loci (Contreras-Galindo et al., 2017Contreras-Galindo R. Dube D. Fujinaga K. Kaplan M.H. Markovitz D.M. Susceptibility of human endogenous retrovirus type K to reverse transcriptase inhibitors.J. Virol. 2017; 91: e01309-e01317Crossref PubMed Scopus (27) Google Scholar). It is likely that no HERVs are able to retrotranspose due to inactivating mutations, although some non-human ERV groups remain active, including intracisternal A-particle (IAP) and endogenous type D murine (MusD) elements in mice. LINE-1s are the sole autonomous mobile DNA in humans, comprising about 17% of our genome. It is estimated that up to 5% of newborns have a new insertion. Although the great majority of L1 copies in humans are inactive, in any individual likely 100 L1s remain retrotransposition-competent. L1s have also been responsible for genomic insertion of about 10,000 processed pseudogenes and over a million non-autonomous short interspersed elements (SINEs). A full-length L1 encodes two proteins from its bicistronic RNA, RNA-binding protein ORF1p and the longer ORF2p, which expresses both DNA endonuclease (EN) and RT activities. Unlike HERVs, whose replication cycle involves reverse transcription of its RNA genome in a cytoplasmic ribonucleoprotein complex, L1-encoded endonuclease nicks the bottom strand of target chromosomal DNA and exposes a 3′-hydoxyl group that serves to prime reverse transcription of the L1 RNA and synthesis of cDNA bound at the site of insertion, a process known as target-primed reverse transcription (TPRT). Several studies previously showed that NRTIs, but only minimally NNRTIs, inhibit LIs (Jones et al., 2008Jones R.B. Garrison K.E. Wong J.C. Duan E.H. Nixon D.F. Ostrowski M.A. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition.PLoS ONE. 2008; 3: e1547Crossref PubMed Scopus (62) Google Scholar, Dai et al., 2011Dai L. Huang Q. Boeke J.D. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition.BMC Biochem. 2011; 12: 18Crossref PubMed Scopus (89) Google Scholar). Inhibitory NRTIs discovered in those studies are now used in investigations of L1 biology. However, in the case of some NRTIs, lack of specificity, off-target effects, or toxicity in cultured cells may muddy conclusions; AZT, for example, can be incorporated into DNA and damage it. In this issue, Garcia-Pérez and colleagues present the most extensive examination to date of the effects of RTis on mammalian endogenous retroelements (Banuelos-Sanchez et al., 2019Banuelos-Sanchez G. Sanchez L. Benitez-Guijarro M. Sanchez-Carnerero V. Salvador-Palomeque C. Tristan-Ramos P. Benkaddour-Boumzaouad M. Morell S. Garcia-Puche J.L. Heras S.R. et al.Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.Cell Chem. Biol. 2019; 26 (this issue): 1095-1109Abstract Full Text Full Text PDF Scopus (19) Google Scholar). They tested the effectiveness of 33 nucleoside analogs, including 15 HIV drugs and other commercially available NTRIs, and 18 pyrimidine analogs synthesized de novo for their study, along with 3 NNTRIs as negative controls, to inhibit activity of human L1s and mouse MusD and IAP ERV elements in established cell culture retrotransposition reporter assays. This comprehensive work considered both short- and long-term cytotoxicity and cataloged retroelement specificity of this class of compounds. Notably, three non-toxic NRTIs were identified that inhibit human LINE-1 but not mouse ERV retrotransposition, including one novel compound designated GBS-149. Curiously, GBS-149 was 18-fold more effective against human over mouse L1s, suggesting structural differences in their RT protein domains that are 75% identical. In general, this paper offers tools for refining future investigations of retroelement action in cells and for better inhibiting RT activity in a clinical setting. RT has cellular consequences beyond retroelement replication, both physiological and pathological. Endogenous L1 RT activity is expressed in murine gametes and embryos, and arguments have been made for roles in preimplantation development and tumor progression, although such important claims call for additional verification (Spadafora, 2016Spadafora C. Soma to germline inheritance of extrachromosomal genetic information via a LINE-1 reverse transcriptase-based mechanism.BioEssays. 2016; 38: 726-733Crossref PubMed Scopus (16) Google Scholar). It has also been reported that experimentally increased expression of L1s promotes fetal oocyte attrition, meiotic defects, and embryonic lethality in mice, phenotypes in part rescued with AZT (Malki et al., 2014Malki S. van der Heijden G.W. O’Donnell K.A. Martin S.L. Bortvin A. A role for retrotransposon LINE-1 in fetal oocyte attrition in mice.Dev. Cell. 2014; 29: 521-533Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Aged cells and mice accumulate cytoplasmic retrotransposon-derived cDNAs triggering an interferon response, while treatment with the NRTIs stavudine (d4T) or lamivudine (3TC) reduces inflammation and increases viability and lifespan (De Cecco et al., 2019De Cecco M. Ito T. Petrashen A.P. Elias A.E. Skvir N.J. Criscione S.W. Caligiana A. Brocculi G. Adney E.M. Boeke J.D. et al.L1 drives IFN in senescent cells and promotes age-associated inflammation.Nature. 2019; 566: 73-78Crossref PubMed Scopus (445) Google Scholar, Simon et al., 2019Simon M. Van Meter M. Ablaeva J. Ke Z. Gonzalez R.S. Taguchi T. De Cecco M. Leonova K.I. Kogan V. Helfand S.L. et al.LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation.Cell Metab. 2019; 29: 871-885.e5Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Other studies have reported that interferon response and neuronal toxicity associated with the childhood encephalopathy Aicardi Goutières Syndrome (AGS) also derive from extrachromosomal L1 cDNAs, a phenomenon again reduced experimentally with stavudine and lamivudine (Thomas et al., 2017Thomas C.A. Tejwani L. Trujillo C.A. Negraes P.D. Herai R.H. Mesci P. Macia A. Crow Y.J. Muotri A.R. Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation.Cell Stem Cell. 2017; 21: 319-331.e8Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Elevated RT levels and expression of HERV-K(HML-2) proteins have been linked with amyotrophic lateral sclerosis (ALS), and the National Institutes of Health is currently conducting a pilot clinical trial designed to target HERV-K RT activity in ALS using the NRTI tenofovir alafenamide, along with protease and integrase inhibitors (clinicaltrials.gov identifier NCT02437110). Similarly, two different AGS-related pilot trials administered abacavir, lamivudine, and AZT (NCT02363452), and tenofovir and emtricitabine (NCT03304717), respectively, to young affected patients. The NCT02363452 trial, now completed, reported reduction in interferon-stimulated gene expression and increase in cerebral blood flow in treated patients (Rice et al., 2018Rice G.I. Meyzer C. Bouazza N. Hully M. Boddaert N. Semeraro M. Zeef L.A.H. Rozenberg F. Bondet V. Duffy D. et al.Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome.N. Engl. J. Med. 2018; 379: 2275-2277Crossref PubMed Scopus (66) Google Scholar). However, these trials would not be able to distinguish effects of inhibiting L1s versus HERVs since tenofovir and AZT suppress both classes of retroelement. Banuelos-Sanchez et al., 2019Banuelos-Sanchez G. Sanchez L. Benitez-Guijarro M. Sanchez-Carnerero V. Salvador-Palomeque C. Tristan-Ramos P. Benkaddour-Boumzaouad M. Morell S. Garcia-Puche J.L. Heras S.R. et al.Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.Cell Chem. Biol. 2019; 26 (this issue): 1095-1109Abstract Full Text Full Text PDF Scopus (19) Google Scholar suggest that abacavir would best be used to identify phenotypic consequences of inhibiting HERV-K RT activity, while the non-toxic cytidine analog inhibitors GBS-149, emtricitabine, and lamivudine are specific inhibitors of L1s. As the authors note, development of even more-specific NRTIs will likely occur once the 3D structure of LINE-1 RT is finally cracked, which has been a difficult task so far. Some potential off-target effects of these efficacious RTis remain to be assessed. In cell culture, NRTIs may inhibit telomerase as well as RT, with consequent shortening of telomeres (Leeansyah et al., 2013Leeansyah E. Cameron P.U. Solomon A. Tennakoon S. Velayudham P. Gouillou M. Spelman T. Hearps A. Fairley C. Smit V. et al.Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging.J. Infect. Dis. 2013; 207: 1157-1165Crossref PubMed Scopus (96) Google Scholar). One should consider the degree to which the RTis investigated by Banuelos-Sanchez et al., 2019Banuelos-Sanchez G. Sanchez L. Benitez-Guijarro M. Sanchez-Carnerero V. Salvador-Palomeque C. Tristan-Ramos P. Benkaddour-Boumzaouad M. Morell S. Garcia-Puche J.L. Heras S.R. et al.Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 Retrotransposons.Cell Chem. Biol. 2019; 26 (this issue): 1095-1109Abstract Full Text Full Text PDF Scopus (19) Google Scholar impact telomerase or DNA polymerases, including inhibition of mitochondrial DNA polymerase gamma, a well-documented off-target of NTRIs. When studying the effects of RT inhibition, one should also keep in mind other retrotransposon-encoded activities. For example, L1 endonuclease cleaves genomic DNA to initiate reverse transcription of L1 RNA. Loss of L1 RT activity could conceivably lead to increased numbers of unresolved EN-induced DNA breaks due to a failure to complete TPRT, and so perhaps precipitate cell apoptosis. Development of a chemical EN inhibitor would help to clarify such effects, and since L1 EN has similarity to apurinic/apyrimidinic (AP)-type endonucleases, testing known AP endonuclease-1 inhibitors in the L1 retrotransposition assay may be a good place to start. With such new inhibitor tools in hand, we can hope to better understand and target the physiological consequences of mobile elements that have through evolution profoundly reordered the human genome and its patterns of expression. Synthesis and Characterization of Specific Reverse Transcriptase Inhibitors for Mammalian LINE-1 RetrotransposonsBanuelos-Sanchez et al.Cell Chemical BiologyMay 30, 2019In BriefThe mobilization of active LINE-1 retrotransposons continues to impact the human genome. LINE-1s move using a copy-and-paste mechanism that relies on reverse transcriptase activity. The identification of compounds that selectively inhibit the reverse transcriptase activity of mammalian LINE-1s will allow studying the impact of their mobilization. Full-Text PDF Open Archive" @default.
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• W2967837582 date "2019-08-01" @default.
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• W2967837582 title "Improved ThwaRTing of Genome Symbionts" @default.
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