The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer

Cell, Journal Year: 2018, Volume and Issue: 172(1-2), P. 275 - 288.e18

Published: Jan. 1, 2018

Language: Английский

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Transcriptional start site heterogeneity modulates the structure and function of the HIV-1 genome

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 113(47), P. 13378 - 13383

Published: Nov. 9, 2016

Significance Current dogma states that the integrated HIV type 1 provirus encodes a single RNA transcript serves as both mRNA for generating viral proteins and genomic is packaged used reverse transcription. We now show multiple transcripts with different functions are generated in infected cells, consequence of heterogeneous transcriptional start site usage. Transcripts begin capped guanosine specifically selected packaging, whereas those two or three guanosines enriched on polysomes translation. In vitro studies recombinant 5′-leader reveal mechanism by which incorporation 5′ dramatically alters structure, function, fate RNA.

Language: Английский

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Nano-DMS-MaP allows isoform-specific RNA structure determination

Nature Methods, Journal Year: 2023, Volume and Issue: 20(6), P. 849 - 859

Published: April 27, 2023

Abstract Genome-wide measurements of RNA structure can be obtained using reagents that react with unpaired bases, leading to adducts identified by mutational profiling on next-generation sequencing machines. One drawback these experiments is short reads rarely mapped specific transcript isoforms. Consequently, information acquired as a population average in regions are shared between transcripts, thus blurring the underlying structural landscape. Here, we present nanopore dimethylsulfate (Nano-DMS-MaP)—a method exploits long-read provide isoform-resolved highly similar molecules. We demonstrate value Nano-DMS-MaP resolving complex landscape human immunodeficiency virus-1 transcripts infected cells. show unspliced and spliced have distinct structures at packaging site within common 5′ untranslated region, likely explaining why viral RNAs excluded from particles. Thus, straightforward resolve biologically important transcript-specific were previously hidden short-read ensemble analyses.

Language: Английский

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Retroviral RNA Dimerization: From Structure to Functions

Frontiers in Microbiology, Journal Year: 2018, Volume and Issue: 9

Published: March 22, 2018

The genome of the retroviruses is a dimer composed by two homologous copies genomic RNA (gRNA) molecules positive polarity. dimerization process allows gRNA to be non-covalently linked together through intermolecular base-pairing. This step critical for viral life cycle and highly conserved among with exception spumaretroviruses. Furthermore, packaging into particles presents an important evolutionary advantage immune system evasion drug resistance. Recent studies reported switches models regulating not only dimerization, but also translation packaging, spatio-temporal characterization within cells are now at hand. review summarizes our current understanding on structural features signals variety (HIVs, MLV, RSV, BLV, MMTV, MPMV…), mechanisms formation functional implications in retroviral cycle.

Language: Английский

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Identification of the initial nucleocapsid recognition element in the HIV-1 RNA packaging signal

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(30), P. 17737 - 17746

Published: July 9, 2020

Significance Understanding the molecular determinants of retroviral genome packaging is important for drug discovery and development vectors gene delivery. We show that HIV-1 leader, which contains RNA elements necessary packaging, binds approximately two dozen copies cognate NC protein with affinities ranging from ∼40 nM to 1.4 µM. Binding four highest-affinity “initial” binding sites occurs endothermic energetics attributed NC-induced localized melting. Mutations stabilize these inhibit in vitro transfected cells. A small-molecule inhibitor specifically initial stabilizes structure. Our findings identify a potential Achilles’ heel HIV therapeutic development.

Language: Английский

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Epitranscriptomic regulation of HIV-1 full-length RNA packaging

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(4), P. 2302 - 2318

Published: Jan. 26, 2022

During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, mechanisms by which HIV-1 Gag protein selects two molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate deposition of N6-methyladenosine (m6A) regulates packaging. While m6A METTL3/METTL14 onto was associated with increased synthesis reduced packaging, FTO-mediated demethylation promoted incorporation viral particles. Interestingly, associates demethylase FTO in nucleus contributes to demethylation. We further identified highly conserved adenosines within 5'-UTR have a crucial functional role methylation packaging Together, our data propose novel epitranscriptomic mechanism allowing selection used genomes.

Language: Английский

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Short- and long-range interactions in the HIV-1 5′ UTR regulate genome dimerization and packaging

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(4), P. 306 - 319

Published: March 28, 2022

Abstract RNA dimerization is the noncovalent association of two human immunodeficiency virus-1 (HIV-1) genomes. It a conserved step in HIV-1 life cycle and assumed to be prerequisite for binding viral structural protein Pr55 Gag during genome packaging. Here, we developed functional analysis structure-sequencing (FARS-seq) comprehensively identify sequences structures within 5′ untranslated region (UTR) that regulate this critical step. Using FARS-seq, found nucleotides important throughout UTR identified distinct conformations monomeric dimeric RNA. In RNA, key domains, such as stem-loop 1 (SL1), polyadenylation signal (polyA) primer site (PBS), folded into independent motifs. SL1 was reconfigured long- short-range base pairings with polyA PBS, respectively. We show these interactions disrupt packaging, additionally PBS–SL1 interaction unexpectedly couples PBS binding. Altogether, our data provide insights late stages mechanistic explanation link between

Language: Английский

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Structure-Activity-Relationship and Mechanistic Insights for Anti-HIV Natural Products

Molecules, Journal Year: 2020, Volume and Issue: 25(9), P. 2070 - 2070

Published: April 29, 2020

Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number deaths Africa. The current therapies achieved success providing instant suppression but with countless undesirable adverse effects. Presently, biodiversity plant kingdom being explored by researchers discovery potent anti-HIV drugs different mechanisms action. primary challenge to afford treatment that free from any sort risk drug resistance and serious side Hence, there strong demand evaluate derived plants as well their derivatives. Several plants, such Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia others displayed significant activity. Here, weattempt summarize main results, focus on structures most plant-based natural products having activity along action IC50 values, structure-activity-relationships important key findings.

Language: Английский

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RNA Structure—A Neglected Puppet Master for the Evolution of Virus and Host Immunity

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: Sept. 19, 2018

The central dogma of molecular biology describes the flow genetic information from DNA to protein via an RNA intermediate. For many years, has been considered simply as a messenger relaying between and proteins. Recent advances in next generation sequencing technology, bioinformatics non-coding have highlighted important roles virtually every biological process. Our understanding further enriched by number significant probing structures. It is now appreciated that cellular viral processes are highly dependent on specific structures / or sequences, such reliance will undoubtedly impact evolution both hosts viruses. As contribution this special issue host immunity virus evolution, it timely consider how sequences could directly influence co-evolution In manuscript, we begin stating some basic principles structures, followed describing critical viruses hosts. More importantly, highlight available new tools predict evaluate novel pointing out limitations readers should be aware their own analyses.

Language: Английский

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5′-Cap sequestration is an essential determinant of HIV-1 genome packaging

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(37)

Published: Sept. 7, 2021

Significance HIV-1 replication is critically dependent on the selective incorporation of viral RNA genomes into assembling virions. Although elements that promote packaging have been identified, determinants authentic fidelity and efficiency until now remained unknown. The present studies show genome selection achieved by a bipartite mechanism requires both dimerization-dependent exposure signals within 5′ leader structural sequestration cap. Cap likely prevents capture cellular processing translation machinery, may help explain why some polymerase III transcripts lack caps can parasitize be commonly employed among viruses package 5′-capped genomes.

Language: Английский

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