The primary focus of this competing renewal application is on the structure and recognition of multi-stranded DNA architectures adopted by guanine plus adenine rich sequences. Such sequences are frequently located within gene regulatory regions and recombination hot spot sites, at the replication origin of signal-stranded bacteriophages, and as tandem repeats in telomeric, centromeric and triplet repeat disease sequences. Such guanine plus adenine rich sequences can align through mismatch, triple orientation of strands and pairing alignments. Our research program applies NMR techniques to architectures, their cation dependent structural transitions and identify unique topologies associated with discriminative recognition. The three areas of focus are: (1) Identification and characterization of base triads involving alignments of two adjacent in-plane bases from one strand (a platform) and a third from a complimentary strand. We propose to elucidate the potential of triad DNA involving stacked triads as a structural motif for the higher order folds of triplet repeat d(GGC)n, d(CAG)n and d(GAA)n disease quadruplex folds in the Tetrahymena telomere d (T2G4)n and mouse Ms6-hm hypervariable microsatellite d(CAG3)n repeats to define the range of strand directionalities, loop connectivities and tetrad alignments. (3) The demonstration and structural characterization of A.(G.G.G.G).A hexads, formed by adenines through in-plane sheared G.A mismatch alignment, with G-tetrads. Such hexad and related octad alignments represent a novel approach towards G-quadruplex recognition and stabilization. G- quadruplexes represent an attractive anti-tumor drug design target since the reverse transcriptase replicative activity of telomerase has an absolute requirement for competing single-stranded telomeric ends.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM034504-15
Application #
6045158
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lewis, Catherine D
Project Start
1984-12-01
Project End
2003-11-30
Budget Start
2000-01-01
Budget End
2000-11-30
Support Year
15
Fiscal Year
2000
Total Cost
$301,878
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Serganov, Alexander; Patel, Dinshaw J (2012) Metabolite recognition principles and molecular mechanisms underlying riboswitch function. Annu Rev Biophys 41:343-70
Kuryavyi, Vitaly; Cahoon, Laty A; Seifert, H Steven et al. (2012) RecA-binding pilE G4 sequence essential for pilin antigenic variation forms monomeric and 5' end-stacked dimeric parallel G-quadruplexes. Structure 20:2090-102
Ren, Aiming; Rajashankar, Kanagalaghatta R; Patel, Dinshaw J (2012) Fluoride ion encapsulation by Mg2+ ions and phosphates in a fluoride riboswitch. Nature 486:85-9
Serganov, Alexander; Patel, Dinshaw J (2012) Molecular recognition and function of riboswitches. Curr Opin Struct Biol 22:279-86
Pikovskaya, Olga; Polonskaia, Anna; Patel, Dinshaw J et al. (2011) Structural principles of nucleoside selectivity in a 2'-deoxyguanosine riboswitch. Nat Chem Biol 7:748-55
Kuryavyi, Vitaly; Patel, Dinshaw J (2010) Solution structure of a unique G-quadruplex scaffold adopted by a guanosine-rich human intronic sequence. Structure 18:73-82
Pikovskaya, Olga; Serganov, Artem A; Polonskaia, Ann et al. (2009) Preparation and crystallization of riboswitch-ligand complexes. Methods Mol Biol 540:115-28
Serganov, Alexander; Patel, Dinshaw J (2009) Amino acid recognition and gene regulation by riboswitches. Biochim Biophys Acta 1789:592-611
Westhof, Eric; Patel, Dinshaw J (2009) Nucleic acids: how high resolution structural biology help us to understand Darwinian evolution. Curr Opin Struct Biol 19:235-8
Lim, Kah Wai; Amrane, Samir; Bouaziz, Serge et al. (2009) Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers. J Am Chem Soc 131:4301-9

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