G-quadruplexes
Nucleic acids are highly flexible molecules than can adopt different conformational structures. While in living systems DNA is largely double helical and RNA is single stranded, guanine-rich sequences can exist in alternative structural forms known as G-quadruplex nucleic acids. We are investigating the functional relevance of a quadruple helical form of nucleic acids and its implication for the biology of nucleic acids. The G-quadruplex hypothesis is of fundamental importance to life and may well hold the key to new therapeutic approaches in numerous areas of human disease that include cancer.
Specific mechanisms under investigation include: DNA G-quadruplex formation at the telomeres and their importance for genomic stability and replication; DNA G-quadruplexes in gene promoters and the regulation of transcription; RNA G-quadruplexes in the untranslated regions of mRNA and the control of protein synthesis (translation).
As part of our studies, we are synthesising new molecules that stabilise the nucleic acid quadruple helix and interfere with specific cellular processes. We make extensive use of biophysical methods (NMR, UV, CD and fluorescence spectroscopy) to study quadruplexes and their interactions with molecules. We are also employing computational methods (bioinformatics) and genomics to explore quadruplexes in genomes.
Key Papers
Selective Photocatalytic C-H oxidation of 5-methylcytosine in DNA
T Yan, Y Chen, B Mortishire-Smith, A Simeone, A Hofer and S Balasubramanian
Angew. Chem. Int. Ed., 2024, e202413593
DOI: 10.1002/anie.202413593
Improved simultaneous mapping of epigenetic features and 3D chromatin structure via ViCAR
S M Flynn, S Dhir, K Herka, C Doyle, L Melidis, A Simeone, W W W Hui, R de Cesaris Araujo Tavares, S Schoenfelder, D Tannahill and S Balasubramanian
Genome Biology., 2024, 25, 237
DOI: 10.1186/s13059-024-03377-6
Transcription-coupled repair of DNA–protein cross-links depends on CSA and CSB
C J Carnie, A C Acampora, A S Bader, C Erdenebat, S Zhao, E Bitensky, D van den Heuvel, A Parnas, V Gupta, G D’Alessandro, M Sczaniecka-Clift, P Weickert, F Aygenli, M J Götz, J Cordes, I Esain-Garcia, L Melidis, A P Wondergem, S Lam, M S Robles, S Balasubramanian, S Adar, M S Luijsterburg, S P Jackson and J Stingele
Nature Cell Biology., 2024, 26, 797-810
DOI: 10.1038/s41556-024-01391-1
An Upstream G-Quadruplex DNA Structure Can Stimulate Gene Transcription
Y Chen, A Simeone, L Melidis, S Martinez Cuesta, D Tannahill and S Balasubramanian
ACS Chem. Biol., 2024, 19, 3, 736-742
DOI: 10.1021/acschembio.3c00775
G-quadruplex DNA structure is a positive regulator of MYC transcription
I Esain-Garcia, A Kirchner, L Melidis, R de Cesaris Araujo Tavares, S Dhir, A Simeone, Z Yu, S K Madden, R Hermann, D Tannahill and S Balasubramanian
PNAS, 2024, 12 (7), e2320240121
DOI: 10.1073/pnas.2320240121
Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity
A Serrano-Benitez, S E Wells, L Drummond-Clarke, L C Russo, J C Thomas, G A Leal, M A Farrow, J M Edgerton, S Balasubramanian, M Yang, C Frezza, A Gautam, J Brazina, K Burdova, N C Hoch, S P Jackson and K W Caldecott
The EMBO Journal., 2023, e113190
DOI: 10.15252/embj.2022223190
