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Structure, Properties, and Biological Relevance of the DNA and RNA G Quadruplexes: Overview 50 Years After Their Discovery

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Structure, Properties, and Biological Relevance of the DNA and RNA G Quadruplexes: Overview 50 Years After Their Discovery ISSN 00062979, Biochemistry (Moscow), 2016, Vol. 81, No. 13, pp. 16021649. © Pleiades Publishing, Ltd., 2016. Original Russian Text © N. G. Dolinnaya, A. M. Ogloblina, M. G. Yakubovskaya, 2016, published in Uspekhi Biologicheskoi Khimii, 2016, Vol. 56, pp. 53154. REVIEW Structure, Properties, and Biological Relevance of the DNA and RNA GQuadruplexes: Overview 50 Years after Their Discovery N. G. Dolinnaya1*, A. M. Ogloblina2, and M. G. Yakubovskaya2 1Lomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia; Email: [email protected] 2Blokhin Cancer Research Center, Institute of Carcinogenesis, Russian Academy of Medical Sciences, 115478 Moscow, Russia Received June 15, 2016 Abstract—Gquadruplexes (G4s), which are known to have important roles in regulation of key biological processes in both normal and pathological cells, are the most actively studied noncanonical structures of nucleic acids. In this review, we summarize the results of studies published in recent years that change significantly scientific views on various aspects of our understanding of quadruplexes. Modern notions on the polymorphism of DNA quadruplexes, on factors affecting thermo dynamics and kinetics of G4 folding–unfolding, on structural organization of multiquadruplex systems, and on conforma tional features of RNA G4s and hybrid DNA–RNA G4s are discussed. Here we report the data on location of G4 sequence motifs in the genomes of eukaryotes, bacteria, and viruses, characterize G4specific smallmolecule ligands and proteins, as well as the mechanisms of their interactions with quadruplexes. New information on the structure and stability of G4s in telomeric DNA and oncogene promoters is discussed as well as proof being provided on the occurrence of Gquadruplexes in cells. Prominence is given to novel experimental techniques (single molecule manipulations, optical and magnetic tweez ers, original chemical approaches, G4 detection in situ, incell NMR spectroscopy) that facilitate breakthroughs in the investigation of the structure and functions of Gquadruplexes. DOI: 10.1134/S0006297916130034 Keywords: Gquadruplex thermodynamics and kinetics, multiquadruplexes, Gquadruplexspecific ligands and proteins, RNA Gquadruplexes, hybrid DNA–RNA Gquadruplexes, telomeric Gquadruplexes, Gquadruplexes in oncogene pro moters The noncanonical DNA structures formed by con lite sequences, as well as in regulatory regions of formational rearrangement of the doublestranded genomes, specifically in oncogene promoters. Data have genome regions with specific base sequences are current been obtained by novel experimental approaches indi ly considered as a novel set of regulatory elements. Four cating that G4 play an important role in regulation of stranded Grich helical structures called the Gquadru key cellular processes [3, 4], such as replication [5, 6], plexes (G4s) are among the most amazing and actively chromosome end protection [7], transcription [8], investigated noncanonical forms of DNA. Gquadru mutagenesis [9], genome damage repair [10], DNA plexes discovered more than half a century ago as a curi recombination [11], and epigenetic processes [12, 13], ous phenomenon of guanosine gel formation now are as well as posttranscriptional events: translation [14], perceived in the scientific mind as an important structur RNA splicing, alternative polyadenylation of mRNA al element of the genome. Currently, G4 formed by RNA [15], and others. molecules have become the subject of intensive studies [1, Many reviews and even books have been dedicated to 2]. the different aspects of G4 formation, their topology, fac Nucleic acid sequences forming G4 (G4motifs) tors affecting stability and polymorphism of these struc have been found in Grich repeats of eukaryotic tures, and interaction of G4s with smallmolecule ligands genomes such as telomeric DNA, micro and minisatel [3, 1618]. However, the number of publications examin ing these noncanonical forms of nucleic acids has grown * To whom correspondence should be addressed. steadily in the last decade, which has been related mainly 1602 GQUADRUPLEXES OF NUCLEIC ACIDS 1603 with progress in investigation of their biological func in investigation of Gquadruplexes and their visualization tions. Interest in G4s is also because their formation is in biological objects. associated with widespread human diseases (cancer, car diovascular diseases, diabetes, neurodegenerative disor ders) [19, 20]. In recent years, G4s have been actively STRUCTURAL FEATURES OF NUCLEIC ACID used as components of nanostructures and lowcost GQUADRUPLEXES AND FACTORS switches that offer promise for applications in nanotech AFFECTING THEIR STABILITY nology and biology [2123]. AND CONFORMATIONAL DIVERSITY Unlike in previous review articles that considered specific issues related to G4s, in this review we summarize G4s are formed via intra or intermolecular inter all aspects of the quadruplex studies. Data from recent actions of DNA or RNA molecules containing tracts of papers that significantly change our notions on the struc oligoG (Gtracts). The central part of a quadruplex tural polymorphism, thermodynamics and kinetics of G4 (core) consists of Gtetrads, in which four guanine folding–unfolding, as well as factors affecting the equilib residues from different strands or different Gtracts (in rium between DNA duplexes and noncanonical four the case of intramolecular G4) are linked through a sys stranded DNAs, and the structural arrangement of multi tem of Hoogsteen hydrogen bonds (more precisely H quadruplexes are analyzed. In addition to these aspects, bonds formed with participation of Watson–Crick and new information on the structure and stability of G4s in Hoogsteen faces of guanine bases). Stacking interac telomeric DNA and oncogene promoters, and on confor tions of planar Gtetrads as well as additional interac mational features of RNA G4 and of hybrid DNA–RNA tions of sugarphosphate backbone fragments [24] form quadruplexes is reviewed. Also we summarized data on the specific G4 structure (Fig. 1). It should be men various classes of ligands recognizing Gquadruplexes, on tioned that the quadruplexlike structures are formed G4specific proteins and antibodies, and on the existence even during selfassociation of guanosine monophos of G4s in vivo. In this review, we present the current state phates. This is related with the specific properties of of nucleic acid Gquadruplex science including a short guanine residues, which have several mutually corre history of the development of our notions on their struc sponding electron donor and electron acceptor centers ture and properties. Special attention was paid to novel and exhibit enhanced capability for stacking interac experimental approaches that provided the breakthrough tions. a Antiparallel Antiparallel Mixed (“3+1”) Parallel (“chair”) (“basket”) b c Propeller Lateral loop Diagonal loop (doublechair reversal) loop Fig. 1. Schematic representation of intramolecular Gquadruplexes differing in strand orientation in the quadruplex core; guanosines in syn conformation are presented in yellow, and in anticonformation – in green (a). Parallelstranded G4 with presented structure of Gtetrads and potassiumbinding sites (black circles) (b). Types of loops that connect Gtracts (c). BIOCHEMISTRY (Moscow) Vol. 81 No. 13 2016 1604 DOLINNAYA et al. In in vitro studies, Gquadruplexes were formed by around the Gquadruplex helix that neutralize the intermolecular interactions of two, three, or four oligonu charges of phosphate groups in the sugarphosphate cleotide molecules containing Gtracts, as well as by backbone contribute only slightly to G4 formation [28]. intramolecular folding of one oligonucleotide molecule Unlike other types of structured nucleic acids, G4 specif (Fig. 1a). A base sequence capable of intramolecular fold ically bind (coordinate) ions of mono and bivalent met 1 2 3 ing into a G4 is usually denoted as G25L G25L G25L G25, als within the highly electronegative central channel where G25 are Gtracts containing from two to five con along the axis of the G4 stem [29]; the cations lose their secutive guanosine residues, and Ln are oligonucleotide hydration shell in the process. That is why the ionic radius linkers connecting these tracts. Until recently, the quadru is a significant factor ensuring the ability of ions to stabi plex core was considered as several righthanded G lize quadruplexes. Information on location of cations tetrads [16]. Only in 2015, a lefthanded Gquadruplex inside the Gquadruplex structure and on the dynamics of analog of ZDNA was discovered using Xray analysis and their binding to DNA was obtained with the NMR spec NMR spectroscopy, which was formed during intramole troscopy and Xray study. The mechanism of a cation cular folding of the d(T(GGT)4TG(TGG)3TGTT) migration into the G4 core was elucidated using molecu oligonucleotide under nearphysiological conditions lar dynamics simulation; it was shown that migration [25]. occurs predominately via the terminal Gtetrads, and the Considerable structural diversity is characteristic for quadruplex loops affect the process. Location of internal DNA G4s due to such factors as the number of forming cations depends on their size and charge. The distance molecules, length of Gtracts, mutual orientation of between the electronegative oxogroups of guanine strands, base sequence (composition) and length of G4 residues in the Gtetrad decreases when a cation enters loops, availability of oligonucleotide fragments flanking
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