Presence, Location and Conservation of Putative G-Quadruplex Forming Sequences in Arboviruses Infecting Humans

Abstract

Guanine quadruplexes (G4s) are non-canonical nucleic acid structures formed by guanine (G)-rich tracts that assemble into a core of stacked planar tetrads. G4s are found in the human genome and in the genomes of human pathogens, where they are involved in the regulation of gene expression and genome replication. G4s have been proposed as novel pharmacological targets in humans and their exploitation for antiviral therapy is an emerging research topic. Here, we report on the presence, conservation and localization of putative G4-forming sequences (PQSs) in human arboviruses. The prediction of PQSs was performed on more than twelve thousand viral genomes, belonging to forty different arboviruses that infect humans, and revealed that the abundance of PQSs in arboviruses is not related to the genomic GC content, but depends on the type of nucleic acid that constitutes the viral genome. Positive-strand ssRNA arboviruses, especially Flaviviruses, are significantly enriched in highly conserved PQSs, located in coding sequences (CDSs) or untranslated regions (UTRs). In contrast, negative-strand ssRNA and dsRNA arboviruses contain few conserved PQSs. Our analyses also revealed the presence of bulged PQSs, accounting for 17–26% of the total predicted PQSs. The data presented highlight the presence of highly conserved PQS in human arboviruses and present non-canonical nucleic acid-structures as promising therapeutic targets in arbovirus infections.

G-Quadruplexes in the Viral Genome: Unlocking Targets for Therapeutic Interventions and Antiviral Strategies

“…A recent genome-wide study led by Nicoletto et al analyzed over 12,000 viral genomes belonging to 40 different human-infecting arboviruses, revealing the presence and conservation of PQSs in these viruses. These findings unveiled the existence of both canonical and bulged PQSs, where bulged PQSs represent a significant proportion, comprising 17-26% of all predicted PQSs in arboviruses [103]. Therefore, a more thorough examination of G4s with long loops is crucial for a better understanding of the functional relevance of non-canonical G4s in viral genomes.…”

“…Until now, research has predominantly focused on conventional G4 structures with loop lengths ranging from 1 to 7 nucleotides. Nevertheless, recent structural investigations have uncovered unconventional G4s (or non-canonical G4s) that deviate from the canonical G4 rules, featuring bulges [70,79,102,103], incomplete G-tetrads (G-triad) [104], and hairpin stem-loop secondary structures [100,105,106]. The overlapping of quadruplex-forming sequences and stem-loop sequences leads to the formation of quadruplex-duplex hybrids, showcasing a blend of their distinctive structural features, and may potentially exhibit novel and unique properties.…”

Special Issue “Bioinformatics of Unusual DNA and RNA Structures”

“…A recent article by Nicoletto et al discusses the presence, conservation, and localization of putative G-quadruplex-forming sequences in human arboviruses [50]. Arboviruses are transmitted by arthropod vectors (arthropod-borne viruses, i.e., arboviruses) and comprise many important human pathogens, including Dengue virus, West Nile virus, Zika virus, or Tick-borne encephalitis virus [51].…”

“…Their study reveals the predominant locations of Gquadruplex-forming sequences in coding sequences and three-prime untranslated regions (3 ′ UTRs). It also highlights their regulatory roles, emphasizing the potential of using G-quadruplex structures as antiviral targets [50].…”

Structure of an RNA G-quadruplex from the West Nile virus genome

“…Since the first detailed reports of quadruplex structures in Tetrahymena telomeric DNA 14 , followed by one in E. coli 5S RNA 15 , numerous studies have demonstrated the presence of G-quadruplexes in a diverse range of organisms and their significant roles in the regulation of cellular processes, such as transcription and genome stability 16 – 18 . Computational studies have identified potential G-quadruplex sites in many viral genomes 18 – 21 including those of the genus Orthoflavivirus , with multiple conserved G-quadruplex sites predicted across the coding regions of these genomes 22 , 23 . Further biophysical studies have shown that some of the predicted G-quadruplex sequences in the ZIKV, tickborne encephalitis virus (TBEV) and WNV genomes are able to form quadruplexes in vitro 22 , 24 – 28 , and treatment of ZIKV or TBEV infected cells with known quadruplex binders has an antiviral effect 25 – 27 .…”