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
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
A Photoredox Reaction for the Selective Modification of 5-Carboxycytosine in DNA
B J Mortishire-Smith, S M Becker, A Simeone, L Melidis and S Balasubramanian
J. Am. Chem. Soc., 2023, early online article
DOI: 10.1021/jacs.2c12558
Selective Functionalisation of 5-Methylcytosine by Organic Photoredox Catalysis
M M Simpson, C C Lam, J M Goodman and S Balasubramanian
Angew. Chemie, 2023, e202304756
DOI: 10.1002/anie.202304756
Simultaneous sequencing of genetic and epigenetic bases in DNA
J Füllgrabe, W S Gosal, P Creed, S Liu, C K Lumby, D J Morley, T W B Ost, A J Vilella, S Yu, H Bignell, P Burns, T Charlesworth, B Fu, H Fordham, N J Harding, O Gandelman, P Golder, C Hodgson, M Li, M Lila, Y Liu, J Mason, J Mellad, J M Monahan, O Nentwich, A Palmer, M Steward, M Taipale, A Vandomme, R S San-Bento, A Singhal, J Vivian, N Wójtowicz, N Williams, N J Walker, N C H Wong, G N Yalloway, J D Holbrook and S Balasubramanian
Nature Biotechnology, 2023, early online article
DOI: 10.1038/s41587-022-01652-0
Chem-map profiles drug binding to chromatin in cells
Z Yu, J Spiegel, L Melidis, W W I Hui, X Zhang, A Radzevičius and S Balasubramanian
Nature Biotechnology, 2023, early online article
DOI: 10.1038/s41587-022-01636-0
Identification of putative reader proteins of 5-methylcytosine and its derivatives in Caenorhabditis elegans RNA
I C Navarro, K M Suen, D Bensaddek, A Tanpure, A Lamond, S Balasubramanian and E A Miska
Wellcome Open Res, 2022, 7:282
DOI: 10.12688/wellcomeopenres.17893.1
