Biochemistry: studies of duplex and quadruplex DNA; bending, flexibility and ligand binding of duplex and damaged DNAs
The structures of quadruplex DNAs formed by aptamer, telomere and triplet DNAs have been studied by this group. We have been able to determine the structures of DNAs containing quadruplexes and have also been able to determine the sites that metal ions occupy when they bind to quadruplex DNAs. We are now looking at drug molecules which specifically bind to quadruplex DNAs, how potassium binding controls quadruplex structure, and how loop length and composition affects quadruplex DNA structure.
The structures of a variety of duplex DNAs containing single damaged sites have been determined. The structures shown above show the surface accessibility of two damaged DNAs, the alpha and beta hemiacetal forms of an abasic site, in a dA tract. These studies are aimed at determining which features of the damaged DNAs can be recognized, which structural features – if any – are common to damaged DNAs and how damaged sites effect the long range structures of DNA.
There are ongoing studies of the bending, curvature and ligand binding of damaged and duplex DNAs. These studies are being carried out by NMR and fluorescence based methods. We are particularly interested in the extent to which DNA bending and flexibility are used in the recognition of duplex and damaged DNAs.
- Arthanari, H., Basu, S., Kawano, T. L., and Bolton, P. H. (1998) “Fluorescent dyes specific for quadruplex DNA” Nucleic Acids Res. 26, 3724-3728 Marathias, B.M., Sawicki, M.J., & Bolton, P.H. (1999) 6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation. Nucleic Acids Res, 27: 1854-58.Marathias, V. M., Jerkovic, B. & Bolton, P.H. (1999). Determinants of DNA Quadruplex Structural Type: Sequence and Potassium Binding. Biochemistry, 38: 4355-64.Jerkovic, B. & Bolton, P.H. (2000). The curvature of dA tracts in temperature dependent [In Process Citation]. Biochemistry, 39: 12121-7Marathias, V. M. & Bolton. (2000).Structures of the potassium –saturated, 2:1, and intermediate, 1:1, forms of quadruplex DNA. Nucleic Acid, 28: 1969-77
Marathias, V.M., Jerkovic, B., Arthanari, H. & Bolton, P.H. (2000). Flexibility and Curvature of Duplex DNA Containing Mismatched Sites as a Function of Temperature. Biochemistry, 39: 153-160.
Arthanari, H. & Bolton P.H. (2001). Functional and dysfunctional roles of quadruplex DNA in cells. Chemistry Biol, 8: 221-30.
Jerkovic, B. & Bolton, P.H. (2001). Magnesium increases the curvature of duplex DNA that contains dA tracts. Biochemistry, 40: 9406-11.
Shiels, J.C., Jerkovic, B., Baranger, A.M. & Bolton, P.H. (2001). RNA-DNA hybrids containing damaged DNA are substrates fro RNase H. Bioorg Med Chem Lett, 11: 2623-6.
Arthanari, H. & Bolton, P.H. (2003). Did quadruplex DNA play a role in the evolution of the eukaryotic linear chromosome? Mini Reve Med Chemistry, 3: 1-9.
Arthanari, H., McConnell, K.J., Beger, R., Young, M.A., Beveridge, D.L. & Bolton, P.H. (2003). Assessment of the molecular dynamics structure of DNA in solution based on calculated and observed NMR NOESY volumes and dihedral angles from scalar coupling constants. Biopolymers, 68: 3-15.
Arthanari, H., Wojtuszewski, K., Mukerji, I., and Bolton P.H. (2004). “Effects of HU binding on the equilibrium cyclization of mismatched, curved, and normal DNA.” Biophys, 86: 1625-1631.
Rujan, I.N. Meleney, J.C., Bolton, P.H. et al. (2005). Vertebrate telomere repeat DNAs favor external loop propeller quadruplex structure in the presence of high concentrations of potassium. Nucleic Acids Research 33: 2002-2031.
Paramasivan, S., Rujan, I, and Bolton, P.H. (2007) Circular dichroism of quadruplex DNAs: Applications to structure, cation effects and ligand binding. Methods.43(4): 324-31.
Vitko J., et al. and Bolton, P.H. (2007) Molecular beacon-equilibrium cyclization detection of DNA-protein complexes. Biophys. J., 93: 3210-17.
Yan, Z., et al. and Bolton, P.H. (2007) Selective recognition on RNA helices containing dangling ends by a quinoline derivative. Chembiochem, 8: 1658-61.
Paramasivan, S. and Bolton, P.H. (2008) Mix and measure fluorescence screening for selective quadruplex binders. Nucleic Acids Research, In Press.
- B.S. 1972 Michigan State University
- Ph.D. 1976 University of California, San Diego