G-quadruplex roles in the pathogenesis of viral diseases (viruses are sorted according to the Baltimore classification, which is based on the process of mRNA synthesis and could be more relevant for G4 effect)

Virus (Name, Family, Genome)Related Gene/ProteinRoleReference
HSV-1 (HHV-1) Herpesviridae ds-DNAa. 500-bp regions flanking the recombination breakpointsa. The recombination breakpoints of HSV-1 are placed adjacent to G4 motifs. G4 clusters are recognized as hot spots for recombination in HSV-1Saranathan et al. (2019)
b. Replication compartmentsb. G4 structures are likely to be involved in the latent phase of viruses with lytic and latent phasesArtusi et al. (2016)
c. Pac-1 (near genome termini)c. Packaging and cleavage of virus and DNA maturation for encapsidationBiswas et al. (2018)
d. IE genesd. Inhibition of transcriptionFrasson et al. (2019)
HSV-2 (HHV-2) Herpesviridae ds-DNAIE genesMultiple stable G4s in both leading and lagging strand were detected, which inhibit transcriptionFrasson et al. (2019)
VZVa (HHV-3) Herpesviridae ds-DNAIE genesMultiple stable G4s in both leading and lagging strand were detected, which inhibit transcriptionFrasson et al. (2019)
EBV (HHV-4) Herpesviridae ds-DNAEBNA1 mRNARegulation of translation. Stabilizing this RNA G4 can be linked with the repression of translation and antiviral activityMurat et al. (2014)
HCMV (HHV-5) Herpesviridae ds-DNAVarious genes (UL34, UL35, UL82, IRS1, US30, UL75 and UL76, TRS1, etc.)Inhibition of transcription. NMM ligand stabilized these G4s and prevented gene expression. Not all G4s in the genome of the virus are involved in the regulation of transcriptionRavichandran et al. (2018)
HHV-6 Herpesviridae ds-DNADirect repeat regions of pac-1 (and probably pac-2) and TMRsUnknown, probably involved in homologous recombination for TMRs; for pac-1 the function is uncharacterized but could be similar to pac-1 in HSV-1Gilbert-Girard et al. (2017)
KSHV (HHV-8) Herpesviridae ds-DNAa. LANA mRNAa. Inhibition of translation and the protein product of this mRNA is involved in the latency of the viruses in host cellsDabral et al. (2020)
b. TR region of DNAb. Replication inhibition. Phen-DC3 unlike TMPyP4 hampered the replication processMadireddy et al. (2016)
HPV Papillomaviridae ds-DNALCR, L1, E1, and E4Possibly a platform for binding of the host transcription factors and regulation of gene expressionTlučková et al. (2013); Puig Lombardi et al. (2019)
SV40 Polyomaviridae ds-DNAA repeat sequence, which plays important role in viral encapsidation and also the coding region of several genes (prM, E, NS1, NS3, NS5)Regulation of replication. SV40 bears a large a multifunctional protein called T-antigen, which is capable of unwinding G4sPatel et al. (2000); Tuesuwan et al. (2008); Mishra et al. (2019)
ZIKVa Flaviviridae (+) ss-RNA3ʹ and 5ʹ of UTR and other sitesUncharacterized but probably important for translation or viral replicationFleming et al. (2016)
HCV Flaviviridae (+) ss-RNAa. Stem-loop IIyʹ of 3ʹ-end of the negative stranda. Prevention of RNA synthesis by the RNA-dependent RNA polymeraseJaubert et al. (2018)
b. HCV core (C) geneb. Nucleolin protein of the host acts as an antiviral protein by binding to HCV core gene G-quadruplex and suppressing its replicationWang et al. (2016a); Bian et al. (2019)
SARS-CoV Coronaviridae (+) ss-RNAORF1 ab, spike (S), ORF3a, membrane (M), and nucleocapsid (N) genes (in SARS-CoV-2)Not defined but inhibition of transcription/replication or translation is the most probable functionBartas et al. (2020); Ji et al. (2020); Panera et al. (2020)
NiVaParamyxoviridae (−) ss-RNAG and L genes, encoding the cell attachment glycoprotein and RNA-dependent RNA polymeraseThese two highly conserved G-quadruplex–forming sequences thwart the replication and may also be of significance for transcriptionMajee et al. (2020)
EBOVa Filoviridae (−) ss-RNAL geneImplicated in the transcription and probably also replication. TMPyP4 stabilizes this structure and inhibits the replication of the virusWang et al. (2016b); Krafčíková et al. (2017b)
FLUAV* Orthomyxoviridae (−) ss-RNAHemagglutinin and neuraminidase genesAlthough G4 formation is not confirmed experimentally, the presence of these G-rich regions might be related to genetic heterogeneityGlazko and Kosovsky (2013)
RVFV Phenuiviridae (−) ss-RNA + ambisense RNA3ʹ-Terminal of the nucleocapsid (N) mRNAEvading the host RNA decay ribonucleases by stalling the activity of XRN1(Charley et al. (2018)
HIV-1 Retroviridae ss-RNA + RTa. LTR promotera. Silencer of transcription and its stabilization is concurrent with decreased virus production(Perrone et al. (2015); Butovskaya et al. (2018)
b. 3ʹ UTRb. Conserved sequences for m6A installation, presumably important for proper viral replicationFleming et al. (2019)
c. Nef genec. Controls the genes expression of Nef protein and stabilizing the related gene represses the Nef gene expression and restricts viral infectivityPerrone et al. (2013b)
d. U3 region of the viral RNAd. Inhibition of reverse transcription, which was suppressed further by BRACO-19Perrone et al. (2014)
e. Gag gene and cPPTe. Along with other G4 structures in the genome, cooperates in the dimerization and adherence of two HIV-1 RNA structuresPiekna-Przybylska et al. (2013)
f. Sp1 binding region in HIV-1 promoterbf. Causing virus latencyPiekna-Przybylska et al. (2020)
HBV Orthohepadnaviridae ds-DNA + RTa. PreS2/S promoter (HBV genotype B or HBV/B)a. This G4 adjusts the transcription of HBV surface antigen levels in a positive manner, unlike routine G4 structuresBiswas et al. (2017)
b. ε stem-loop structure of 3ʹ end of RNA (HBV)b. A location for the installation of m6A is interleaved between two tetrad PQSs, which is involved in increased translation and decreased reverse transcriptionImam et al. (2018)
  • a EBOV, Ebola virus; FLUAV, influenza A virus; VZV, varicella zoster virus; ZIKV, Zika virus.

  • b Sp1-binding region is part of LTR in HIV-1.

  • * G4 formation is not verified experimentally for FLUAV.