What do G-quadruplexes in viral genomes tell us?

G-quadruplexes are structural elements that can form in both DNA and RNA molecules. They are formed by guanine-rich sequences that fold into very stable four-stranded structures. G-quadruplexes have been identified in various biological contexts, including genomes of viruses. In viral genomes, G-quadruplexes are proposed as important elements which play a role in viral genome stability (by protecting viral DNA from degradation and recombination events), regulation of gene expression (by affecting transcription and translation processes, in viral genomes, G-quadruplexes can be found in promoter regions and other regulatory sequences), but they are suggested also as antiviral targets (targeting G-quadruplexes can disrupt critical viral processes, such as replication and gene expression, leading to inhibition of viral proliferation). Therefore, the development of small molecules that specifically interact with G-quadruplex structures in viral genomes is a broad research area with therapeutic potential.

Using the G4Hunter tool (https://bioinformatics.ibp.cz/#/), we have analyzed H1N1 influenza genomes (1), all Nidovirales genomes, including SARSC-CoV2 (2, 3), and all genomes accessible in the NCBI Genome database (4). Our result shows that G-quadruplex-prone sequences are not distributed randomly in viral genomes, but that they are associated with function regions; moreover, we have shown that the presence of the G-quadruplexes is correlated with the type of viral infection. The presence of G-quadruplex sequences is related to viral life cycles and corresponds to the type of viral infection rather than the type of nucleic acid; while viruses that cause persistent infections are enriched for G-quadruplex-prone sequences, viruses that cause acute infections have a significantly reduced number of G-quadruplexes (4). Furthermore, we found a significant positive correlation between the frequencies of G-quadruplex-prone sequences in dsDNA viruses and the corresponding hosts of archaea, bacteria and eukaryotes (5). The strong relationship between the G-quadruplex-prone sequences in the virus and the host indicates a close coevolution and an evolutionarily reciprocal imitation of the genome organization (5, 6).

1. Brázda,V., Porubiaková,O., Cantara,A., Bohálová,N., Coufal,J., Bartas,M., Fojta,M. and Mergny,J.-L. (2021) G-quadruplexes in H1N1 influenza genomes. BMC Genomics, 22, 77.

2. Bartas,M., Brázda,V., Bohálová,N., Cantara,A., Volná,A., Stachurová,T., Malachová,K., Jagelská,E.B., Porubiaková,O., Červeň,J., et al. (2020) In-Depth Bioinformatic Analyses of Nidovirales Including Human SARS-CoV-2, SARS-CoV, MERS-CoV Viruses Suggest Important Roles of Non-canonical Nucleic Acid Structures in Their Lifecycles. Front. Microbiol., 11, 1583.

3. Bidula,S. and Brázda,V. (2023) Genomic Analysis of Non-B Nucleic Acids Structures in SARS-CoV-2: Potential Key Roles for These Structures in Mutability, Translation, and Replication? Genes, 14, 157.

4. Bohálová,N., Cantara,A., Bartas,M., Kaura,P., Šťastný,J., Pečinka,P., Fojta,M., Mergny,J.-L. and Brázda,V. (2021) Analyses of viral genomes for G-quadruplex forming sequences reveal their correlation with the type of infection. Biochimie, 186, 13–27.

5. Bohálová,N., Cantara,A., Bartas,M., Kaura,P., Šťastný,J., Pečinka,P., Fojta,M. and Brázda,V. (2021) Tracing dsDNA Virus-Host Coevolution through Correlation of Their G-Quadruplex-Forming Sequences. Int. J. Mol. Sci., 22, 3433.

6. Brázda,V., Dobrovolná,M., Bohálová,N. and Mergny,J.-L. G-quadruplexes in the evolution of hepatitis B virus. Nucleic Acids Res., 2023.