Seaman, F. C., & Hurley, L. H. (1999). 31P-Nmr as a probe for drug-nucleic acid interactions. Phosphorus, Sulfur and Silicon and Related Elements, 144-146, 297-300.
Abstract:
The structural impact of covalent and noncovalent interactions of drugs with DNA is an important component for understanding the biochemical and biological consequences of DNA damage. Work in this laboratory has focused on a number of potentially therapeutically important drugs that distort DNA by unwinding, bending DNA into the major or minor groove. These lead to enhanced recognition of DNA by proteins involved in transcription and replication. In this paper, we will present the structures of one of these complexes and show how 31P-NMR can be used to monitor these distortive effects.
Hurley, L., Brown, R. V., & Hurley, L. -. (2011). DNA acting like RNA. Biochemical Society transactions, 39(2).
Over the last decade or so, secondary non-B-DNA structures such as G-quadruplexes and i-motifs have come into focus as biologically functioning moieties that are potentially involved in telomeric interactions and the control of gene expression. In the present short review, we first describe the structural and dynamic parallels with complex RNA structures, including the importance of sequence and ions in folding, and then we describe the biological consequences of the folded structures. We conclude that there are considerable parallels between secondary and tertiary structures in RNA and DNA from both the folding and the biological perspectives.
Sun, D., & Hurley, L. H. (2010). Biochemical techniques for the characterization of G-quadruplex structures: EMSA, DMS footprinting, and DNA polymerase stop assay.. Methods in molecular biology (Clifton, N.J.), 608, 65-79.
PMID: 20012416;PMCID: PMC2797547;Abstract:
The proximal promoter region of many human growth-related genes contains a polypurine/polypyrimidine tract that serves as multiple binding sites for Sp1 or other transcription factors. These tracts often contain a guanine-rich sequence consisting of four runs of three or more contiguous guanines separated by one or more bases, corresponding to a general motif known for the formation of an intramolecular G-quadruplex. Recent results provide strong evidence that specific G-quadruplex structures form naturally within these polypurine/polypyrimidine tracts in many human promoter regions, raising the possibility that the transcriptional control of these genes can be modulated by G-quadruplex-interactive agents. In this chapter, we describe three general biochemical methodologies, electrophoretic mobility shift assay (EMSA), dimethylsulfate (DMS) footprinting, and the DNA polymerase stop assay, which can be useful for initial characterization of G-quadruplex structures formed by G-rich sequences.
Seaman, F. C., Chu, J., & Hurley, L. (1996). Erratum: Cross-linkage by 'intact' bizelesin and bisalkylation by the 'separated halves' of the bizelesin dimer: Contrasting drug manipulation of DNA conformation (5'-TAATTA-3') directs alkylation toward different adenine targets (J. Am. Chem. Soc. 1996, 118, 5383-5395). Journal of the American Chemical Society, 118(33), 7871-.
Hurley, L., Kim, M., Vankayalapati, H., Shin-Ya, K., Wierzba, K., & Hurley, L. -. (2002). Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex. Journal of the American Chemical Society, 124(10).
Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules. In this communication we provide the first experimental evidence that telomestatin selectively facilitates the formation of or stabilizes intramolecular G-quadruplexes, in particular, that produced from the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking approach was used to study the binding interactions of telomestatin with the intramolecular antiparallel G-quadruplex structure. Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results). A 2:1 model for the telomestatin bound in the external stacking mode in an energy minimized complex with the human telomeric basket-type G-quadruplex was constructed. Our observation that a G-quadruplex-interactive molecule without significant groove interactions is able to reorient in a G-quadruplex structure proints to the importance of core interaction with an asymmetric G-quadruplex structure in producing selective binding. Furthermore, the G-quadruplex interactions of telomestatin are more selective for the intramolecular structure in contrast to other G-quadruplex-interactive agents, such as TMPyP4.
