Structural properties of DNA G-quadruplexes with applications in colloidal assembly

G-quadruplexes are complex DNA structures formed by guanine rich sequences. Such structures have the potential to form in many important regions of the genome such as telomere ends, promoter regions of many oncogenes. They exhibit a wide range of topologies depending on the nature of the sequences. In this work, we studied a number of sequences with interrupted G-tracts which were thought to disfavor the formation of G-quadruplexes. We found that many of these sequences form G-quadruplexes defying conventional rules. This thesis also addresses micro-particle assembly using DNA. Magnetic micro-particles have been connected with DNA quadruplexes to form long chains. This is supplemented by a study of dissociation of these particle chains in the presence of quadruplex binding ligands​Doctor of Philosophy (SPMS

Bulges in G‑Quadruplexes: Broadening the Definition of G‑Quadruplex-Forming Sequences

We report on the first solution structure of an intramolecular G-quadruplex containing a single bulge and present evidence for extensive occurrence of bulges in different G-quadruplex contexts. The NMR solution structure of the d­(TTGTGGTGGGTGGGTGGGT) sequence reveals a propeller-type parallel-stranded G-quadruplex containing three G-tetrad layers, three double-chain-reversal loops, and a bulge. All guanines participate in the formation of the G-tetrad core, despite the interruption between the first guanine and the next two guanines by a thymine, which forms a single-residue bulge and is projected out of the G-tetrad core. To provide a more general understanding about the formation of bulges within G-quadruplexes, we systematically investigated the effects of the residue type, the size, the position, and the number of bulges on the structure and stability of G-quadruplexes. The formation of bulges has also been observed in two different G-quadruplex scaffolds with different strand orientations and folding topologies. Our results show that bulges can be formed in many different situations within G-quadruplexes. While many sequences tested in this study can form stable G-quadruplex structures, all of them defy the description of sequences G₃₊N_L1G₃₊N_L2G₃₊N_L3G₃₊, currently used in most bioinformatics searches for identifying potential G-quadruplex-forming sequences in the genomes. Broadening of this description to include the possibilities of bulge formation should allow the identification of more G-quadruplex-forming sequences which went unnoticed in the earlier searches. This study could also open the possibilities of exploiting bulges as recognition elements for interactions between G-quadruplexes and other molecules

Dataset of bulged G-quadruplex forming sequences in the human genome

When several continuous guanine runs are present closely in a nucleic acid sequence, a secondary structure called G-quadruplex can form (G4s). Such structures in the genome could serve as structural and functional regulators in gene expression, DNA-protein binding, epigenetic modification, and genotoxic stress. Several types of G4-forming DNA sequences exist, including bulged G4-forming sequences (G4-BS). Such bulges occur due to the presence of non-guanine bases in specific locations (G-runs) in the G4-forming sequences. At present, search algorithms do not identify stable G4-BS conformations, making genome-wide studies of G4-like structures difficult. Data provided in this study are related to a published article ''Stable bulged G-quadruplexes in the human genome: Identification, experimental validation and functionalization'' published by Nucleic Acids Research [DIO.org/10.193/nar/gkad252]. Based on our studies in vitro and G4-seq and G4 CUT&Tag data analysis, we have specified and validated three pG4-BS models. In this article, a large collection of 'raw' (unfiltered) dataset is presented, which includes three subfamilies of pG4-BS. For each of pG4-BS, we provide strand-specific genomic boundaries. Data on pG4-BS might be useful in elucidating their structural, functional, and evolutionary roles. Furthermore, they may provide insight into the pathobiology of G4-like structures and their potential therapeutic applications

Stable bulged G-quadruplexes in the human genome: identification, experimental validation and functionalization

DNA sequence composition determines the topology and stability of G-quadruplexes (G4s). Bulged G-quadruplex structures (G4-Bs) are a subset of G4s characterized by 3D conformations with bulges. Current search algorithms fail to capture stable G4-B, making their genome-wide study infeasible. Here, we introduced a large family of computationally defined and experimentally verified potential G4-B forming sequences (pG4-BS). We found 478 263 pG4-BS regions that do not overlap 'canonical' G4-forming sequences in the human genome and are preferentially localized in transcription regulatory regions including R-loops and open chromatin. Over 90% of protein-coding genes contain pG4-BS in their promoter or gene body. We observed generally higher pG4-BS content in R-loops and their flanks, longer genes that are associated with brain tissue, immune and developmental processes. Also, the presence of pG4-BS on both template and non-template strands in promoters is associated with oncogenesis, cardiovascular disease and stemness. Our G4-BS models predicted G4-forming ability in vitro with 91.5% accuracy. Analysis of G4-seq and CUT&Tag data strongly supports the existence of G4-BS conformations genome-wide. We reconstructed a novel G4-B 3D structure located in the E2F8 promoter. This study defines a large family of G4-like sequences, offering new insights into the essential biological functions and potential future therapeutic uses of G4-B.Agency for Science, Technology and Research (A*STAR)Nanyang Technological UniversityPublished versionBioinformatics Institute, Biomedical Institutes/A-STAR, Singapore (in part); V.A.K. was supported by a SUNY EMPIRE innovation program scholar grant; Upstate Medical University Cancer Center grant; Upstate Foundation Turn4ACure Fund; research in A.T.P. lab was supported by Nanyang Technological University Singapore; P.J. was supported by the Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation (OPS MHESI); Thailand Science Research and Innovation (TSRI) [RGNS 64-161]. Funding for open access charge: SUNY EMPIRE innovation program scholar grant, the Upstate Medical University Cancer Center grant; Upstate Foundation Turn4ACure Fund

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

10.1007/s00018-020-03620-wCellular and Molecular Life Sciences7841837-185

Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation (Genome Biology, (2021), 22, 1, (167), 10.1186/s13059-021-02375-2)

10.1186/s13059-021-02405-zGenome Biology22118

Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

10.1186/s13059-021-02375-2GENOME BIOLOGY22