HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR

Klase, Zachary; Kale, Prachee; Winograd, Rafael; Gupta, Madhur V; Heydarian, Mohammad; Berro, Reem; McCaffrey, Timothy A.; Kashanchi, Fatah

doi:10.1186/1471-2199-8-63

Cited by 224 publications

(258 citation statements)

References 105 publications

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“…Interestingly, several studies have revealed the existence of retroviral HIV-1-encoded miRNAs. Klase et al (37) showed that processing of the HIV-1 TAR element creates a miRNA that contributes to viral latency. Further work is in progress to identify the in vivo target repertoire of the complete BLV miRNA cluster and elucidate its function.…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma

Rosewick

Momont

Durkin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

135

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Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III)-transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5′-LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent ∼40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation.noncoding RNA | oncogenesis | retrovirus silencing | HTLV-1

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Section: Discussionmentioning

confidence: 99%

Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma

Rosewick

Momont

Durkin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

135

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“…The low amount of TAR and RRE vsiRNAs identified by various groups may prove to be of importance during a relatively short time frame at the beginning of HIV-1 RNA expression. 49,[72][73][74][75] The displacement of endogenous miRNAs into the RISC mediated by TAR or RRE competition may contribute to mechanisms leading to changes in gene expression and associated pathogenicity in patients.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

et al. 2015

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Several proteins and RNAs expressed by mammalian viruses have been reported to interfere with RNA interference (RNAi) activity. We investigated the ability of the HIV-1-encoded RNA elements Trans-Activation Response (TAR) and RevResponse Element (RRE) to alter RNAi. MicroRNA let7-based assays showed that RRE is a potent suppressor of RNAi activity, while TAR displayed moderate RNAi suppression. We demonstrate that RRE binds to TAR-RNA Binding Protein (TRBP), an essential component of the RNA Induced Silencing Complex (RISC). The binding of TAR and RRE to TRBP displaces small interfering (si)RNAs from binding to TRBP. Several stem-deleted RRE mutants lost their ability to suppress RNAi activity, which correlated with a reduced ability to compete with siRNA-TRBP binding. A lentiviral vector expressing TAR and RRE restricted RNAi, but RNAi was restored when Rev or GagPol were coexpressed. Adenoviruses are restricted by RNAi and encode their own suppressors of RNAi, the Virus-Associated (VA) RNA elements. RRE enhanced the replication of wild-type and VA-deficient adenovirus. Our work describes RRE as a novel suppressor of RNAi that acts by competing with siRNAs rather than by disrupting the RISC. This function is masked in lentiviral vectors co-expressed with viral proteins and thus will not affect their use in gene therapy. The potent RNAi suppressive effects of RRE identified in this study could be used to enhance the expression of RNAi restricted viruses used in oncolysis such as adenoviruses.

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“…1A). TAR is a regulatory viral RNA element located at the 5′ end of the HIV-1 retroviral genome that plays many roles in viral replication, including transcription elongation (21), translation (22), dimerization (23), packaging (23), and viral latency (24). TAR contains two functionally important motifs that are separated by four Watson-Crick base pairs: a trinucleotide bulge and a hexanucleotide apical loop (25,26) (Fig.…”

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confidence: 99%

Invisible RNA state dynamically couples distant motifs

Lee

Dethoff

Al‐Hashimi

2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Using on-and off-resonance carbon and nitrogen R1ρ NMR relaxation dispersion in concert with mutagenesis and NMR chemical shift fingerprinting, we show that the transactivation response element RNA from the HIV-1 exists in dynamic equilibrium with a transient state that has a lifetime of ∼2 ms and population of ∼0.4%, which simultaneously remodels the structure of a bulge, stem, and apical loop. This is accomplished by a global change in strand register, in which bulge residues pair up with residues in the upper stem, causing a reshuffling of base pairs that propagates to the tip of apical loop, resulting in the creation of three noncanonical base pairs. Our results show that transient states can remodel distant RNA motifs and possibly give rise to mechanisms for rapid long-range communication in RNA that can be harnessed in processes such as cooperative folding and ribonucleoprotein assembly.NMR spectroscopy | dynamics | R1ρ relaxation dispersion | nucleic acids I t is now well-established that RNA sequences do not code for a single static structure, but rather, many conformations that populate energetic minima along a free-energy landscape (1, 2). Cellular inputs, ranging from changes in temperature and pH to the binding of proteins, other RNAs, and ligands, can preferentially stabilize select conformations along the landscape, resulting in dynamic changes in RNA structure that drive the multistep catalytic cycles of ribozymes (3), regulatory activities of riboswitches (4) and other RNA-based switches (5), and the dynamic assembly and disassembly of ribonucleoprotein (RNP) complexes (6).A common mode of RNA dynamics involves rearrangements in secondary structure that can melt or create entire hairpins, and thereby expose or sequester key regulatory elements that are several nucleotides long (1,4,7,8). Such secondary structural transitions entail large kinetic barriers, so they are often catalyzed by RNA-binding proteins (9), ATP-dependent chaperones (10), or otherwise occur by modulating cotranscriptional folding (5, 11). Recently, NMR R1ρ relaxation dispersion experiments (12-15) in concert with mutagenesis (16) have helped uncover more labile RNA secondary structural transitions that can take place without assistance from external cofactors at rates that are 2-4 orders of magnitude faster than larger-scale secondary structural rearrangements. These transitions entail excursions away from the energetically favorable ground state (GS) toward lowpopulated (typically populations <15%) and short-lived (lifetime < milliseconds) species often referred to as "excited states" (ES) (12, 13). These invisible RNA ES feature localized reshuffling of base pairing in and around noncanonical motifs such as bulges, internal loops, and apical loops (16) which can also expose or sequester functionally important residues or promote ATPindependent large-scale changes in secondary structure (14, 15). These faster and more localized changes in secondary structure may meet unique demands in RNA-based regulatory functions (16).Using...

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HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR

Cited by 224 publications

References 105 publications

Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma

Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

Invisible RNA state dynamically couples distant motifs

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