The Molecular Tête‐à‐Tête between G‐Quadruplexes and the i‐motif in the Human Genome

Abstract

G‐Quadruplex (GQ) and i‐motif structures are the paradigmatic examples of nonclassical tetrastranded nucleic acids having multifarious biological functions and widespread applications in therapeutics and material science. Recently, tetraplexes emerged as promising anticancer targets due to their structural robustness, gene‐regulatory roles, and predominant distribution at specific loci of oncogenes. However, it is arguable whether the i‐motif evolves in the complementary single‐stranded region after GQ formation in its opposite strand and vice versa. In this review, we address the prerequisites and significance of the simultaneous and/or mutually exclusive formation of GQ and i‐motif structures at complementary and sequential positions in duplexes in the cellular milieu. We discussed how their dynamic interplay Sets up cellular homeostasis and exacerbates carcinogenesis. The review gives insights into the spatiotemporal formation of GQ and i‐motifs that could be harnessed to design different types of reporter systems and diagnostic platforms for potential bioanalytical and therapeutic intervention.

A Combined Experimental and Computational Study of Halogen and Hydrogen Bonding in Molecular Salts of 5-Bromocytosine

“…Comparison of selected geometrical parameters of compounds containing the planar 5-bromocytosinium cation shows that the independent molecules have almost equivalent geometry, as the differences among the corresponding bond distances and angles are in the range 0.019–0.040 (13) Å and 2.0–3.7 (10)°, respectively (hereafter the standard uncertainties of the differences have been calculated as the square root of the sum of the squares of the estimated standard deviations of geometrical parameters reported in Table 7 , [ 66 ]). The N3 protonation reflects in the C4–N3–C2 bond angle, which is significantly larger than the corresponding one, 120.2° (6), for neutral 5-bromocytosine, BRCYTS [ 25 ], by 4.5–6.5 (8)°. This difference is fully consistent with the VSEPR theory, according to which the steric requirements of the lone pair on deprotonated aza nitrogen atom implies a wider region than the covalent bond N + −H.…”

“…A remarkable example of structural versatility due to the nucleobase protonation is offered by the intercalated motif ( i -motif) in DNA. In the i -motif, based on the association of cytosine molecules protonated under neutral or slightly acidic conditions to form neutral cytosine—hemi-protonated cytosine base pairs (C:CH + ), two parallel-stranded duplexes are held together in an antiparallel orientation by intercalated C:CH + pairs [ 22 , 23 , 24 , 25 ]. Noteworthy, by decreasing the proton affinity of the N3 atom, 5-halogenation of 1-methylcytosine does not destroy the i -motif in DNA, but may alter the number of trinucleotide repeats required to induce the structural conversion from Watson and Crick ( WC ) base-pairing to the i -motif association [ 26 ].…”

Evolution of Diverse Strategies for Promoter Regulation

“…Cytosine-rich i-motifs are four-stranded local DNA structures that are often located on the opposite strand of DNA from that containing G-quadruplex motifs [64]. There is ongoing debate about whether G-quadruplexes and i-motifs can coexist in the promoter regions or whether they are mutually exclusive in vivo [65].…”

Time-resolved NMR-spectroscopic studies of conformational dynamics in DNA G-quadruplexes

“…[232][233][234] A steric hindrance and differences in their different requirements for stability at physiological conditions impedes a simultaneous formation. 235 However, the i-motif structure itself is highly dynamic. It can switch between hairpin and i-motif conformations in the C-rich strand, which affects the formation of G-quadruplexes in the complementary strand and the recognition by protein binding partners (such as hnRNP-LL).…”

“…81,[236][237][238][239] The influence of chemical and mechanical factors on i-motif and G4 formation has been studied in detail for the G4 forming sequence in the cMYC promoter (NHE-III 1 , 2.4.2), 240 and the general requirements for a simultaneous formation and the possibility for a co-existence have been reviewed recently. 235 Unsurprisingly, the population of either of the structures is dependent on ion-concentrations and pH, but interestingly also on factors like superhelicity and molecular crowding. 234,239,241 Most important to note is that the equilibrium between G4, i-motif and duplex DNA is highly competitive and dynamic.…”