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Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Structural Transition in the Human Telomeric DNA Sequence d[(TTAGGG)4] upon interaction With Putative Anticancer Agents, Sanguinarine And Ellipticine

Even though there have been several studies of interaction between DNA and antcancer agents (1-4), not very much is known about their interactions with the telomeric regions of chromosomes. Guanine rich sequences fold into a non-canonical structure known as G-quartet in the presence of appropriate salt concentration. G-quartets stack on one another to form G-quadruplex. G-rich sequences are found in the telomeric regions of chromosomes and play an important role in chromosome duplication. They are potential targets for anticancer drugs (5). Here we have reported the structural transition of G-quadruplex induced by two putative anticancer agents, Sanguinarine (SGR) and Ellipticine (ELP), from plant sources.

SGR binds with the human telomeric DNA sequence d[(TTAGGG)4] (H24) in the presence of K+ with a 2:1 binding stoichiometry possibly via the end stacking mechanism. Studies based on CD spectroscopy have indicated that at higher concentration (above 20 μM) SGR induces a structural alteration in H24. The structure of H24 changes from the mixed Type-I conformation to the Na+ -conformation (6). ELP also binds with H24. At lower concentrations (100 nM) it binds with 3:2 stoichiometry (ELP : H24) as suggested from Jobs’ Plot based on fluorescence measurements. But at higher ellipticine concentration (8 μM), it binds with a stoichiometry of 2:1 (ELP : H24) and a relatively lower affinity. CD spectroscopic studies suggest that at higher concentrations of drug, H24 undergoes a structural change from the mixed Type-I conformation to the Na+ -conformation. Similar studies from other group (7) along with our results suggest that G-quadruplex interacting drugs probably induce a structural change at higher drug concentration. It could be a plausible molecular mechanism of the action of G-quadruplex binding drugs that interferes with normal biological activities.

References

  1. N. P. Bazhulina, A. M. Nikitin, S. A. Rodin, A. N. Surovaya, Yu. V. Kravatsky, V. F. Pismensky, V. S. Archipova, R. Martin, G. V. Gursky. J Biomol Struct Dyn 26, 701-718 (2009).
  2. G. Singhal, M. R. Rajeswari. J Biomol Struct Dyn 26, 625-636 (2009).
  3. B. Jin, H. M. Lee, S. K. Kim, J Biomol Struct Dyn 27, 457-464 (2010).
  4. H. M. Lee, B. Jin, S. W. Han, S. K. Kim, J Biomol Struct Dyn 28, 421-430 (2010).
  5. S. Ghosh, P. Majumder, S. K. Pradhan, D. Dasgupta, Biochim Biophys Acta 1799, 795-809 (2010).
  6. S. K. Pradhan, D. Dasgupta, G. Basu, Biochem Biophys Res Comun (in press).
  7. R. D. Gray, J. Li, J. B. Chaires, J Phys Chem B 113, 2676-2683 (2009).


Saptaparni Ghosh1, *
Suman Kalyan Pradhan1, 2
Gautam Basu3
Dipak Dasgupta1, *

1Biophysics Division
Saha Institute of Nuclear Physics
Block-AF, Sector-I
Bidhannagar, Kolkata 700064, India
2Section of Molecular Biology
UC San Diego
9500 Gilman
Dr. La Jolla, CA 92093
3Department of Biophysics
Bose Institute
P-1/12 CIT Scheme VIIM
Kolkata 700054, India

ph + 91 33 23370379
fax + 91 33 23376347
saptaparni.ghosh@saha.ac.in dipak.dasgupta@saha.ac.in