G-quadruplexes formed by Varicella-Zoster virus reiteration sequences suppress expression of glycoprotein C and regulate viral cell-to-cell spread

Abstract

G-quadruplex (G4) formed by repetitive guanosine-rich sequences plays important roles in diverse cellular processes; however, its roles in viral infection are not fully understood. In this study, we investigated the genome-wide distribution of G4-forming sequences (G4 motifs) in Varicella-Zoster virus (VZV) and found that G4 motifs are enriched in the internal repeat short and the terminal repeat short regions flanking the unique short region and also in some reiteration (R) sequence regions. A high density of G4 motifs in the R2 region was found on the template strand of ORF14, which encodes glycoprotein C (gC), a virulent factor for viral growth in skin. Analyses such as circular dichroism spectroscopy, thermal difference spectra, and native polyacrylamide gel electrophoresis with oligodeoxynucleotides demonstrated that several G4 motifs in ORF14 form stable G4 structures. In transfection assays, gC expression from the G4-disrupted ORF14 gene was increased at the transcriptional level and became more resistant to suppression by G4-ligand treatment. The recombinant virus containing the G4-disrupted ORF14 gene expressed a higher level of gC mRNA, while it showed a slightly reduced growth. This G4-disrupted ORF14 virus produced smaller plaques than the wild-type virus. Our results demonstrate that G4 formation via reiteration sequences suppresses gC expression during VZV infection and regulates viral cell-to-cell spread.

G-Quadruplexes in the Regulation of Viral Gene Expressions and Their Impacts on Controlling Infection

“…A notably high concentration of G4 motifs is present on the template strand within ORF14, responsible for encoding glycoprotein C (gC), which is a virulent agent essential for viral growth in skin cells. G4 formation through the reiteration sequence results in suppressed gC expression during VZV infection and results in the regulation of viral cell-to-cell transmission [161].…”

Deciphering Preferential Binding Interaction of Synthetic Pyrido[2,3‐c]Carbazole Alkaloid Derivative (PCAD) with Pu24T G‐quadruplex DNA

“…Such findings suggest that GQ structures may be critical for the control of several biological processes, such as telomere preservation, transcription, translation, replication and more. [5,6,7] Over the last few decades, researchers have investigated tiny compounds that generate or stabilize GQ complexes, which might be a powerful anti-cancer treatment that acts by downregulating oncogenic expressions. [8,9,10] Alkaloids, as a type of natural product, are among the most fundamental organic substances engaged in critical physiological functions and may be found in plants, animals, and microbes.…”

Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target

“…The G4 structure consists of stacking tetrads composed of four guanine bases connected by Hoogsteen hydrogen bonds ( 18 , 19 ). Growing evidence indicates the presence of G4s in viral genomes, including pseudorabies virus ( 20 , 21 , 22 , 23 ), HIV ( 24 ), Epstein-Barr virus ( 25 ), human papillomavirus ( 26 ), hepatitis B virus ( 27 ), HSV ( 28 ), Nipah virus ( 29 ), hepatitis C virus (HCV) ( 30 ), Zika virus ( 31 , 32 ), Ebola virus ( 33 ), chikungunya virus ( 34 ), enterovirus A71 ( 35 ), Kaposi’s sarcoma-associated herpes virus ( 36 ), varicella-Zoster virus ( 37 ), severe acute respiratory syndrome (SARS)-CoV ( 38 ), and SARS-CoV-2 ( 39 , 40 ). These G4 structures play vital roles in regulating virus replication, transcription, and translation.…”