Adventures with Four-Stranded DNA structures

Dr Zoe Waller, University of East Anglia. Part of the chemistry organic seminar series.

 

DNA can adopt many different conformations and amongst the best-studied are G-quadruplexes, four-stranded secondary structures formed from sequences rich in guanine.1 The regions of DNA which form in the cytosine-rich sequences opposite G-quadruplexes are also able to form i-motifs, also four stranded structures comprised of parallel-stranded DNA duplexes connected in an anti-parallel orientation by intercalated, cytosine–cytosine base pairs.2 i-Motifs are stabilised by acidic conditions, which promote C-C base pairing via hemi-protonation of the N3; folding is rapid and this property has been utilised in many different nanotechnological applications. It is often assumed that i-motif formation is dependent on low pH, but there have always been examples where they are still present under neutral conditions.3 There are also now cases where i-motif can form at neutral and slightly alkaline pH depending on the types of sequence,4,5 conditions6-8 and the presence of ligands.9 Moreover, there are examples of stabilisation of i-motif structures resulting in disruption of telomerase10 and enhancement of gene expression.11

Here we describe work in our group towards the stabilisation of four-stranded DNA structures and their applications in nanotechnology and biology.

References:

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2. K. Gehring, J. L. Leroy, M. Gueron, Nature 1993, 363, 561.
3. J-L. Mergny, L. Lacroix, X. Han, J-L. Leroy, C. Helene J. Am. Chem. Soc., 1995, 117, 8887.
4. J. A. Brazier, A. Shah, G. D. Brown, Chem. Commun. 2012, 48, 10739.
5. E. P. Wright, J. L. Huppert and Z. A. E. Waller, Nucleic Acids Res., 2017, 45, 2951.
6. A. Rajendran, S. Nakano, and N. Sugimoto Chem. Commun. 2010, 46, 1299.
7. H. A. Day, C. Huguin, Z. A. E. Waller, Chem. Commun. 2013, 49, 7696
8. H. A. Day, E. P. Wright, C. J. Macdonald, A. J. Gates,  Z. A. E. Waller, Chem. Commun. 2015, 51, 14099.
9. E. P. Wright, H. A. Day, A. M. Ibrahim, J. Kumar, L. J. E. Boswell, C. Huguin, C. E. M. Stevenson, K. Pors, Z. A. E. Waller Sci. Rep. 2016, 6, 39456.
10. Y. Chen, K. Qu, C. Zhao, L. Wu, J. Ren, J. Wang, X. Qu, Nat. Commun. 2012, 3, 1074
11. S. Kendrick, H. J. Kang, M. P. Alam, M. M. Madathil, P. Agrawal, V. Gokhale, D. Yang, S. M. Hecht, L. H. Hurley, J. Am. Chem. Soc. 2014, 136, 4161.