The role of local DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, the significance of G-quadruplexes was demonstrated in the last decade, and their presence and functional relevance has been demonstrated in many genomes, including humans. In this study, we analyzed the presence and locations of G-quadruplex-forming sequences by G4Hunter in all complete bacterial genomes available in the NCBI database. G-quadruplex-forming sequences were identified in all species, however the frequency differed significantly across evolutionary groups. The highest frequency of G-quadruplex forming sequences was detected in the subgroup Deinococcus-Thermus, and the lowest frequency in Thermotogae. G-quadruplex forming sequences are non-randomly distributed and are favored in various evolutionary groups. G-quadruplex-forming sequences are enriched in ncRNA segments followed by mRNAs. Analyses of surrounding sequences showed G-quadruplex-forming sequences around tRNA and regulatory sequences. These data point to the unique and non-random localization of G-quadruplex-forming sequences in bacterial genomes.

Department of Biology and Ecology Institute of Environmental Technologies Faculty of Science University of Ostrava 710 00 Ostrava Czech Republic

Department of Informatics Mendel University in Brno Zemedelska 1665 1 61300 Brno Czech Republic

Faculty of Chemistry Brno University of Technology Purkyňova 118 612 00 Brno Czech Republic

Faculty of Mechanical Engineering Brno University of Technology Technicka 2896 2 616 69 Brno Czech Republic

Institute of Biophysics Academy of Sciences of the Czech Republic v v i Královopolská 135 612 65 Brno Czech Republic

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Watson J.D., Crick F.H. Molecular structure of nucleic acids. Nature. 1953;171:737–738. doi: 10.1038/171737a0. PubMed DOI

Szlachta K., Thys R.G., Atkin N.D., Pierce L.C.T., Bekiranov S., Wang Y.-H. Alternative DNA secondary structure formation affects RNA polymerase II promoter-proximal pausing in human. Genome Biol. 2018;19:89. doi: 10.1186/s13059-018-1463-8. PubMed DOI PMC

Brázda V., Laister R.C., Jagelská E.B., Arrowsmith C. Cruciform structures are a common DNA feature important for regulating biological processes. BMC Mol. Biol. 2011;12:33. doi: 10.1186/1471-2199-12-33. PubMed DOI PMC

Sun Z.-Y., Wang X.-N., Cheng S.-Q., Su X.-X., Ou T.-M. Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction. Molecules. 2019;24:396. doi: 10.3390/molecules24030396. PubMed DOI PMC

Nelson L.D., Bender C., Mannsperger H., Buergy D., Kambakamba P., Mudduluru G., Korf U., Hughes D., Van Dyke M.W., Allgayer H. Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer. Mol. Cancer. 2012;11:38. doi: 10.1186/1476-4598-11-38. PubMed DOI PMC

Gellert M., Lipsett M.N., Davies D.R. Helix Formation by Guanylic acid. Proc. Natl. Acad. Sci. USA. 1962;48:2013–2018. doi: 10.1073/pnas.48.12.2013. PubMed DOI PMC

Harkness R.W., Mittermaier A.K. G-quadruplex dynamics. Biochim. Biophys. Acta Proteins Proteom. 2017;1865:1544–1554. doi: 10.1016/j.bbapap.2017.06.012. PubMed DOI

Siddiqui-Jain A., Grand C.L., Bearss D.J., Hurley L.H. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl. Acad. Sci. USA. 2002;99:11593–11598. doi: 10.1073/pnas.182256799. PubMed DOI PMC

Lee S.C., Zhang J., Strom J., Yang D., Dinh T.N., Kappeler K., Chen Q.M. G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress. Mol. Cell. Biol. 2016;37:e00122-16. doi: 10.1128/MCB.00122-16. PubMed DOI PMC

Endoh T., Kawasaki Y., Sugimoto N. Stability of RNA quadruplex in open reading frame determines proteolysis of human estrogen receptor α. Nucleic Acids Res. 2013;41:6222–6231. doi: 10.1093/nar/gkt286. PubMed DOI PMC

Lam E.Y.N., Beraldi D., Tannahill D., Balasubramanian S. G-quadruplex structures are stable and detectable in human genomic DNA. Nat. Commun. 2013;4:1796. doi: 10.1038/ncomms2792. PubMed DOI PMC

Long X., Stone M.D. Kinetic Partitioning Modulates Human Telomere DNA G-Quadruplex StructuralPolymorphism. PLoS ONE. 2013;8:e83420. doi: 10.1371/journal.pone.0083420. PubMed DOI PMC

Sun D., Thompson B., Cathers B.E., Salazar M., Kerwin S.M., Trent J.O., Jenkins T.C., Neidle S., Hurley L.H. Inhibition of human telomerase by a G-Quadruplex-Interactive compound. J. Med. Chem. 1997;40:2113–2116. doi: 10.1021/jm970199z. PubMed DOI

Lee H.-S., Carmena M., Liskovykh M., Peat E., Kim J.-H., Oshimura M., Masumoto H., Teulade-Fichou M.-P., Pommier Y., Earnshaw W.C., et al. Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy. Cancer Res. 2018;78:6282–6296. doi: 10.1158/0008-5472.CAN-18-0894. PubMed DOI PMC

Dickerhoff J., Onel B., Chen L., Chen Y., Yang D. Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length. ACS Omega. 2019;4:2533–2539. doi: 10.1021/acsomega.8b03580. PubMed DOI PMC

Balasubramanian S., Hurley L.H., Neidle S. Targeting G-quadruplexes in gene promoters: A novel anticancer strategy? Nat. Rev. Drug Discov. 2011;10:261–275. doi: 10.1038/nrd3428. PubMed DOI PMC

Cimino-Reale G., Zaffaroni N., Folini M. Emerging Role of G-quadruplex DNA as Target in Anticancer Therapy. Curr. Pharm. Design. 2016;22:6612–6624. doi: 10.2174/1381612822666160831101031. PubMed DOI

Asamitsu S., Obata S., Yu Z., Bando T., Sugiyama H. Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy. Molecules. 2019;24:429. doi: 10.3390/molecules24030429. PubMed DOI PMC

Yoshida W., Saikyo H., Nakabayashi K., Yoshioka H., Bay D.H., Iida K., Kawai T., Hata K., Ikebukuro K., Nagasawa K., et al. Identification of G-quadruplex clusters by high-throughput sequencing of whole-genome amplified products with a G-quadruplex ligand. Sci. Rep. 2018;8:1–8. doi: 10.1038/s41598-018-21514-7. PubMed DOI PMC

Brázda V., Hároníková L., Liao J.C.C., Fojta M. DNA and RNA Quadruplex-Binding Proteins. Int. J. Mol. Sci. 2014;15:17493–17517. doi: 10.3390/ijms151017493. PubMed DOI PMC

Mishra S.K., Tawani A., Mishra A., Kumar A. G4IPDB: A database for G-quadruplex structure forming nucleic acid interacting proteins. Sci. Rep. 2016;6:38144. doi: 10.1038/srep38144. PubMed DOI PMC

Brázda V., Cerveň J., Bartas M., Mikysková N., Coufal J., Pečinka P. The amino acid composition of quadruplex binding proteins reveals a shared motif and predicts new potential quadruplex interactors. Molecules. 2018;23:2341. doi: 10.3390/molecules23092341. PubMed DOI PMC

Patro L.P.P., Kumar A., Kolimi N., Rathinavelan T. 3D-NuS: A web server for automated modeling and visualization of non-canonical 3-dimensional nucleic acid structures. J. Mol. Biol. 2017;429:2438–2448. doi: 10.1016/j.jmb.2017.06.013. PubMed DOI

Huppert J.L., Balasubramanian S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 2005;33:2908–2916. doi: 10.1093/nar/gki609. PubMed DOI PMC

Eddy J., Maizels N. Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res. 2006;34:3887–3896. doi: 10.1093/nar/gkl529. PubMed DOI PMC

Bedrat A., Lacroix L., Mergny J.L. Re-evaluation of G-quadruplex propensity with G4Hunter. Nucleic Acids Res. 2016;44:1746–1759. doi: 10.1093/nar/gkw006. PubMed DOI PMC

diCenzo G.C., Finan T.M. The Divided Bacterial Genome: Structure, Function, and Evolution. Microbiol. Mol. Biol. Rev. 2017;81:e00019-17. doi: 10.1128/MMBR.00019-17. PubMed DOI PMC

Yadav V.K., Abraham J.K., Mani P., Kulshrestha R., Chowdhury S. QuadBase: Genome-wide database of G4 DNA—Occurrence and conservation in human, chimpanzee, mouse and rat promoters and 146 microbes. Nucleic Acids Res. 2008;36:D381–D385. doi: 10.1093/nar/gkm781. PubMed DOI PMC

König S.L.B., Huppert J.L., Sigel R.K.O., Evans A.C. Distance-dependent duplex DNA destabilization proximal to G-quadruplex/i-motif sequences. Nucleic Acids Res. 2013;41:7453–7461. doi: 10.1093/nar/gkt476. PubMed DOI PMC

Mishra S.K., Jain N., Shankar U., Tawani A., Sharma T.K., Kumar A. Characterization of highly conserved G-quadruplex motifs as potential drug targets in Streptococcus pneumoniae. Sci. Rep. 2019;9:1791. doi: 10.1038/s41598-018-38400-x. PubMed DOI PMC

Rawal P., Kummarasetti V.B.R., Ravindran J., Kumar N., Halder K., Sharma R., Mukerji M., Das S.K., Chowdhury S. Genome-wide prediction of G4 DNA as regulatory motifs: Role in Escherichia coli global regulation. Genome Res. 2006;16:644–655. doi: 10.1101/gr.4508806. PubMed DOI PMC

Neidle S. The structures of quadruplex nucleic acids and their drug complexes. Curr. Opin. Struct. Biol. 2009;19:239–250. doi: 10.1016/j.sbi.2009.04.001. PubMed DOI

Saranathan N., Vivekanandan P. G-Quadruplexes: More than just a kink in microbial genomes. Trends Microbiol. 2018;27:148–163. doi: 10.1016/j.tim.2018.08.011. PubMed DOI PMC

Kaplan O.I., Berber B., Hekim N., Doluca O. G-quadruplex prediction in E. coli genome reveals a conserved putative G-quadruplex-Hairpin-Duplex switch. Nucleic Acids Res. 2016;44:9083–9095. PubMed PMC

Brocchieri L. The GC Content of Bacterial Genomes. J. Phylogenet. Evolut. Biol. 2013;2:1–3. doi: 10.4172/2329-9002.1000e108. DOI

Ding Y., Fleming A.M., Burrows C.J. Case studies on potential G-quadruplex-forming sequences from the bacterial orders Deinococcales and Thermales derived from a survey of published genomes. Sci. Rep. 2018;8:15679. doi: 10.1038/s41598-018-33944-4. PubMed DOI PMC

Brumm P.J., Monsma S., Keough B., Jasinovica S., Ferguson E., Schoenfeld T., Lodes M., Mead D.A. Complete Genome Sequence of Thermus aquaticus Y51MC23. PLoS ONE. 2015;10:e0138674. doi: 10.1371/journal.pone.0138674. PubMed DOI PMC

Waller Z.A.E., Pinchbeck B.J., Buguth B.S., Meadows T.G., Richardson D.J., Gates A.J. Control of bacterial nitrate assimilation by stabilization of G-quadruplex DNA. Chem. Commun. 2016;52:13511–13514. doi: 10.1039/C6CC06057A. PubMed DOI PMC

Čechová J., Lýsek J., Bartas M., Brázda V. Complex analyses of inverted repeats in mitochondrial genomes revealed their importance and variability. Bioinformatics. 2018;34:1081–1085. doi: 10.1093/bioinformatics/btx729. PubMed DOI PMC

Brázda V., Kolomazník J., Lýsek J., Hároníková L., Coufal J., Št’astný J. Palindrome analyser—A new web-based server for predicting and evaluating inverted repeats in nucleotide sequences. Biochem. Biophys. Res. Commun. 2016;478:1739–1745. doi: 10.1016/j.bbrc.2016.09.015. PubMed DOI

Brázda V., Lýsek J., Bartas M., Fojta M. Complex Analyses of Short Inverted Repeats in All Sequenced Chloroplast DNAs. BioMed Res. Int. 2018;2018:1097018. doi: 10.1155/2018/1097018. PubMed DOI PMC

Ruggiero E., Richter S.N. G-quadruplexes and G-quadruplex ligands: Targets and tools in antiviral therapy. Nucleic Acids Res. 2018;46:3270–3283. doi: 10.1093/nar/gky187. PubMed DOI PMC

Chen B.-J., Wu Y.-L., Tanaka Y., Zhang W. Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics. Int. J. Biol. Sci. 2014;10:1084–1096. doi: 10.7150/ijbs.10190. PubMed DOI PMC

Belmonte-Reche E., Martínez-García M., Guédin A., Zuffo M., Arévalo-Ruiz M., Doria F., Campos-Salinas J., Maynadier M., López-Rubio J.J., Freccero M., et al. G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents. J. Med. Chem. 2018;61:1231–1240. doi: 10.1021/acs.jmedchem.7b01672. PubMed DOI PMC

Li F., Mulyana Y., Feterl M., Warner J.M., Collins J.G., Keene F.R. The antimicrobial activity of inert oligonuclear polypyridylruthenium(II) complexes against pathogenic bacteria, including MRSA. Dalton Trans. 2011;40:5032–5038. doi: 10.1039/c1dt10250h. PubMed DOI

Li F., Grant Collins J., Richard Keene F. Ruthenium complexes as antimicrobial agents. Chem. Soc. Rev. 2015;44:2529–2542. doi: 10.1039/C4CS00343H. PubMed DOI

Xu L., Chen X., Wu J., Wang J., Ji L., Chao H. Dinuclear Ruthenium(II) Complexes That Induce and Stabilise G-Quadruplex DNA. Chem. Eur. J. 2015;21:4008–4020. doi: 10.1002/chem.201405991. PubMed DOI

Xu L., Zhang D., Huang J., Deng M., Zhang M., Zhou X. High fluorescence selectivity and visual detection of G-quadruplex structures by a novel dinuclear ruthenium complex. Chem. Commun. 2010;46:743–745. doi: 10.1039/B918045A. PubMed DOI

Wilson T., Williamson M.P., Thomas J.A. Differentiating quadruplexes: Binding preferences of a luminescent dinuclear ruthenium (II) complex with four-stranded DNA structures. Org. Biomol. Chem. 2010;8:2617–2621. doi: 10.1039/b924263e. PubMed DOI

Codd G.A., Lindsay J., Young F.M., Morrison L.F., Metcalf J.S. Harmful Cyanobacteria. Springer; Dordrecht, The Netherlands: 2005. Harmful cyanobacteria; pp. 1–23.

Perrone R., Lavezzo E., Riello E., Manganelli R., Palù G., Toppo S., Provvedi R., Richter S.N. Mapping and characterization of G-quadruplexes in Mycobacterium tuberculosis gene promoter regions. Sci. Rep. 2017;7:5743. doi: 10.1038/s41598-017-05867-z. PubMed DOI PMC

Lavezzo E., Berselli M., Frasson I., Perrone R., Palù G., Brazzale A.R., Richter S.N., Toppo S. G-quadruplex forming sequences in the genome of all known human viruses: A comprehensive guide. PLOS Comput. Biol. 2018;14:e1006675. doi: 10.1371/journal.pcbi.1006675. PubMed DOI PMC

Beaume N., Pathak R., Yadav V.K., Kota S., Misra H.S., Gautam H.K., Chowdhury S. Genome-wide study predicts promoter-G4 DNA motifs regulate selective functions in bacteria: Radioresistance of D. radiodurans involves G4 DNA-mediated regulation. Nucleic Acids Res. 2013;41:76–89. doi: 10.1093/nar/gks1071. PubMed DOI PMC

Kota S., Dhamodharan V., Pradeepkumar P.I., Misra H.S. G-quadruplex forming structural motifs in the genome of Deinococcus radiodurans and their regulatory roles in promoter functions. Appl. Microbiol. Biotechnol. 2015;99:9761–9769. doi: 10.1007/s00253-015-6808-6. PubMed DOI

Repoila F., Darfeuille F. Small regulatory non-coding RNAs in bacteria: Physiology and mechanistic aspects. Biol. Cell. 2009;101:117–131. doi: 10.1042/BC20070137. PubMed DOI

Brázda V., Kolomazník J., Lýsek J., Bartas M., Fojta M., Št’astný J., Mergny J.-L. G4Hunter web application: A web server for G-quadruplex prediction. Bioinformatics. 2019:btz087. doi: 10.1093/bioinformatics/btz087. PubMed DOI PMC

Sayers E.W., Agarwala R., Bolton E.E., Brister J.R., Canese K., Clark K., Connor R., Fiorini N., Funk K., Hefferon T., et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2019;47:D23–D28. doi: 10.1093/nar/gky1069. PubMed DOI PMC

Federhen S. The NCBI taxonomy database. Nucleic Acids Res. 2011;40:D136–D143. doi: 10.1093/nar/gkr1178. PubMed DOI PMC

Letunic I., Bork P. Interactive tree of life (iTOL) v3: An online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 2016;44:W242–W245. doi: 10.1093/nar/gkw290. PubMed DOI PMC

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