Research Projects

G-quadruplexes (G4s) are formed by the association of guanines, involved in normal cellular processes (Varshney et al., 2020). The unconventional loops/bulges have expanded the repertoire of G4s (Mukundan and Phan, 2013). My PhD research investigated putative G4s in the promoters of ZEB1 and MAPK12 oncogenes to understand G4 transcriptional regulation (Dutta et al., 2021; Sengupta et al., 2024). G4-sites are protein-binding hotspots and associate with R-loops to promote CTCF binding (Wulfridge et al., 2023). RNA/DNAs form ‘kissing complexes’, where the unpaired nucleotides in one stem-loop base pairs with the unpaired nucleotides in another RNA/DNA (Barbault et al., 2002;Cao and Chen, 2011). G4s composed of long loops may be involved in complementary base pairing with other G4s. G4 ‘loop: loop’ kissing complexes have not yet been established. Interacting G4s forming ‘G4-kissing complexes’ (G4k) may imply enhanced protein recognition specificity. Ligand/protein specificity relies on its interaction with the G4 loops(Campbell et al., 2009); the variable unit of G4 (Meier-Stephenson, 2022; Shu et al., 2022). G4BPs in general have a significant proportion of disordered regions, and the binding of which to transient/dynamic G4s is well noted (Papageorgiou et al., 2023), supporting the formation of biomolecular condensates (Feng et al., 2019; Sahoo et al., 2024). Few structures are available for G4-bound protein complexes, limiting the understanding of precise molecular interactions. These have been classified as domains of G4BPs like RGGs , RRMs , helicase cores, and Zn-fingers (Shu et al., 2022). Research indicates that typically only 5-6 residues of DNA are recognized by patches of protein domains at a time, which form H-bonding (Chakraborty et al., 2025; Nair and Madhusudhan, 2022). This presents potential G4 loop binding interactions with proteins, even other G4s and G4 binding molecules. This essence was captured in one of my co-author studies, where an unusual 8-nt loop forming ORAI1 promoter G4, housed a potential E-box motif that bound ZEB1 (Chatterjee et al., 2024). Hence, the G4 loops are unexplored for their potential as specific hotspots for binding ligands, G4BPs, or even other G4 structures. Nucleolus is a membrane-less organelle, involved in ribosome biogenesis (RiBi), that has emerged as a promising anti-cancer target. For example, CX-5461 gained much attention as a TOP II poison, RNA Pol-I inhibitor and G4 stabilizer that blocks RiBi, implicated in cancer treatment (Dharmaiah et al., 2025; Li et al., 2025; Xu and Hurley, 2022). Although CX-5461 has been approved for FDA fast-track designation for the treatment HRD breast and ovarian cancers, we have yet to understand its precise effects of G4 stabilization. CX-5461 may have an impact on the formation of G4k that perturb condensate formation, contributing to the accumulation of potential off-target effects.