biomedical sciences research institute - Research - University of Ulster

Dr Mateus Webba da SilvaLecturer in Pharmaceutical ChemistryContact Details:T: +44 (0)28 70324009mm.webba-da-silva@ulster.ac.ukMost of cellular DNA exists as a double-helix composed of A:T and G:C base pairings.However, nucleic acids can also adopt other architectures. In particular, G-rich sequencescan fold into four-stranded structures denominated G-quadruplexes. Dr Silva’s generalinterests reside in the application of nucleic acids structural & chemical biology tobiomedical problems. Current areas of interest include (i) understanding the role ofG-quadruplex folds in regulation of gene expression; and (ii) design of nucleic acidarchitectures for biomedical and biotechnological applications.Recently, evidence has emerged suggesting that quadruplex architectures regulate geneexpression. Dr Silva and his team have identified putative quadruplex folding regions in aseries of human genes with crucial regulatory functions, investigated the propensity forquadruplex folding utilizing and developing biochemical, biophysical and molecular biology methods, and identifiedligands that selectively target some of these architectures. In these studies they have developed the means to modulatethe productivity of select genes that affect human conditions and disease states. In particular they established theinnate propensity of G-quadruplex folding of a region containing transcription factor binding sites within the proximalpromoter of fibroblast growth factor 2 (FGF2 also known as bFGF). This gene encodes a protein with roles in broadangiogenic, mitogenic, and neurotrophic activities. It is the most extensively studied growth factor and is involvedin numerous cellular functions in various cell types, including angiogenesis, cell proliferation, cell differentiation,tumorigenesis, tissue remodeling, wound healing, and limb formation. They developed methodology to directly assessformation of a specific topology/structure within the context of the double helical region, established the propensityof a DNA segment of a gene to fold into a G-quadruplex. They have thus demonstrated how propensity of a primarysequence to form an identified quadruplex topology perturbs the equilibrium between the closed double helix andopen single strands. Studies on modulation of gene expression continue on systems in vivo.Dr Silva’s team has also identified a set of ligands that induce and/or stabilize the folding of a G-quadruplex in theproximal promoter of OTX2. The orthodenticle homeobox 2 gene (OTX2) encodes a member of the bicoid subfamilyof homeodomain-containing transcription factors. Recently it has been established that OTX2 overexpressioncan trigger a critical period of neuronal plasticity. Modulating regulation of OTX2 expression is believed to playa role in enhancing mental agility in old age, help treat neurological disorders as diverse as Alzheimer’s, stroke,schizophrenia, and autism. These studies continue towards the development of drugs that can up-regulate or downregulateOTX2 expression.Dr Silva’s team is developing fundamental rules for prediction, design and control self-assembly of DNA G-quadruplextopologies. They have translated some of these rules into computational algorithms that have been used to design abinitio a series of small quadruplex topologies (15-35 nucleotides) with exciting properties: they are extremely resistantto DNAse 1 and S1-nuclease, do not denature in the presence of known denaturants, and do not disassemble evenin boiling aqueous considitions! They are currently being investigated towards some biomedical and biotechnologicalapplications.Publications:Webba da Silva M; Geometric formalism for DNA quadruplex folding; Chem. Eur. J., 13: 9738-9745, 2007Webba da Silva M; NMR methods for studying quadruplex nucleic acids; Methods, 43: 264-277, 200718