Visualization of DNA G-quadruplexes in herpes simplex virus 1-infected cells

Artusi, Sara; Perrone, Rosalba; Lago, Sara; Raffa, Paolo; Iorio, Enzo Di; Palù, Giorgio; Richter, Sara N.

doi:10.1093/nar/gkw968

Cited by 63 publications

(87 citation statements)

References 66 publications

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“…As regards the GGG-island type, the herpesvirus family of dsDNA viruses presents PQSs distributed along all the four identified genomic features, with a particularly high concentration in RR and, in some members, in the 5'-regulatory region. This feature is consistent with the reported extent of G4s in HSV-1, which are mainly clustered in the RR of the virus genome [12,13]. Conversely, viruses belonging to the ssRNA (+) and ssRNA (-) classes show PQSs mainly grouped in CDS and in the 3'-and 5'-regulatory regions, respectively.…”

Section: Human Virus Pqss Position and Overlap With Genomic Featuressupporting

confidence: 90%

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G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide

et al. 2018

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G-quadruplexes are non-canonical nucleic-acid structures that control transcription, replication, and recombination in organisms. G-quadruplexes are present in eukaryotes, prokaryotes, and viruses. In the latter, mounting evidence indicates their key biological activity. Since data on viruses are scattered, we here present a comprehensive analysis of potential quadruplex-forming sequences (PQS) in the genome of all known viruses that can infect humans. We show that occurrence and location of PQSs are features characteristic of each virus class and family. Our statistical analysis proves that their presence within the viral genome is orderly arranged, as indicated by the possibility to correctly assign up to two-thirds of viruses to their exact class based on the PQS classification. For each virus we provide: i) the list of all PQS present in the genome (positive and negative strands), ii) their position in the viral genome, iii) the degree of conservation among strains of each PQS in its genome context, iv) the statistical significance of PQS abundance. This information is accessible from a database to allow the easy navigation of the results: http://www.medcomp.medicina.unipd.it/main_site/doku.php?id=g4virus. The availability of these data will greatly expedite research on G-quadruplex in viruses, with the possibility to accelerate finding therapeutic opportunities to numerous and some fearsome human diseases.

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Section: Human Virus Pqss Position and Overlap With Genomic Featuressupporting

confidence: 90%

“…The presence of G4s in viruses and their involvement in virus key steps is increasingly evident in most of the Baltimore groups [10,11]. In the dsDNA group, G4s were described in both Herpesviridae and Papillomaviridae families [12][13][14][15][16][17][18][19][20]. In ssDNA viruses, the presence of G4s was reported in the adeno-associated virus genome [21].…”

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G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide

et al. 2018

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“…Relative binding affinity, analyzed by MS competition assay for un2, un3, gp054a, hTel21, c-kit2 (kit), c-myc (myc) and HIV-1 LTR-III G4-folded oligonucleotides. replication 28 . During this step they likely control both viral replication itself and other key processes of the infection, with consequent dramatic effect when they are stabilized by c-exNDI.…”

Section: Discussionmentioning

confidence: 99%

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro

Perrone

Scalabrin

et al. 2017

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G-quadruplexes (G4s) are nucleic acids secondary structures, epigenetic regulators in cells and viruses. In herpes simplex virus 1 (HSV-1)-infected cells, G4s are massively present during viral replication. We here aimed at investigating the possibility to target the HSV-1 G4s by a core extended naphtalene diimide (c-exNDI) G4 ligand. Biophysical and biomolecular analysis proved that c-exNDI stabilized the HSV-1 G4s in a concentration dependent manner. In MS competition assays, c-exNDI preferentially recognized HSV-1 G4s over cellular telomeric G4s, the most represented G4s within cells; other less abundant cellular G4s were also recognized. Treatment of HSV-1 infected cells with c-exNDI at low nanomolar concentrations induced significant virus inhibition with no cytotoxicity. The mechanism of action was ascribed to G4-mediated inhibition of viral DNA replication, with consequent impairment of viral genes transcription. Our data suggest that the observed potent antiviral activity and low cytotoxicity mainly depend on a combination of c-exNDI affinity for HSV-1 G4s and their massive presence during infection. HSV-1 G4s may thus represent new effective antiviral targets: the fact that no current antiherpetic drug exploits them and their presence at the viral genome, responsible for both active and latent HSV infections, makes them particularly attracting.

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“…Among herpesviruses, RNA G4s have been implicated in the regulation of DNA replication and translation of the Epstein–Barr virus1213. We have shown that the herpes simplex virus 1 possesses several repeats of sequences forming stable G4s, which were visualized in infected cells by a G4-specific antibody14; stabilization of these tetraplex structures by a G4 ligand inhibited viral DNA replication15.…”

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The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes

Scalabrin

Frasson

Ruggiero

et al. 2017

Sci Rep

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G-quadruplexes are four-stranded conformations of nucleic acids that act as cellular epigenetic regulators. A dynamic G-quadruplex forming region in the HIV-1 LTR promoter represses HIV-1 transcription when in the folded conformation. This activity is enhanced by nucleolin, which induces and stabilizes the HIV-1 LTR G-quadruplexes. In this work by a combined pull-down/mass spectrometry approach, we consistently found hnRNP A2/B1 as an additional LTR-G-quadruplex interacting protein. Surface plasmon resonance confirmed G-quadruplex specificity over linear sequences and fluorescence resonance energy transfer analysis indicated that hnRNP A2/B1 is able to efficiently unfold the LTR G-quadruplexes. Evaluation of the thermal stability of the LTR G-quadruplexes in different-length oligonucleotides showed that the protein is fit to be most active in the LTR full-length environment. When hnRNP A2/B1 was silenced in cells, LTR activity decreased, indicating that the protein acts as a HIV-1 transcription activator. Our data highlight a tightly regulated control of transcription based on G-quadruplex folding/unfolding, which depends on interacting cellular proteins. These findings provide a deeper understanding of the viral transcription mechanism and may pave the way to the development of drugs effective against the integrated HIV-1, present both in actively and latently infected cells.

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Visualization of DNA G-quadruplexes in herpes simplex virus 1-infected cells

Cited by 63 publications

References 66 publications

G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide

G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes

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