Multistranded DNAs: Structures, Transitions, Recognition

Sloan-Kettering Inst Can Research, New York NY

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Abstract

This competing renewal outlines a research program that applies NMR and x-ray crystallographic approaches to the structures, transitions and recognition of multistranded DNA architectures. New motifs identified during the last renewal ranged from triads, to mixed tetrads, pentads and hexads, as well as double chain reversal loops and V-shaped scaffolds. New motifs currently under investigation include G*G*G triple platforms, mixed G*A*G*A tetrads, duplex-quadruplex junctions and mini triad DNA. A new project will address the structures and interconversions between competing quadruplex folds adopted by a guanine repeat-containing oncogenic c-myc promotor element. We have determined the structure of a novel dimeric interdigitated quadruplex containing double chain reversal loops, which targets the core domain of HIV-1 integrase with nanomolar affinity. Studies of complex formation are currently underway and should elucidate the principles by which this very stable scaffold projects unique bases for potential targeting of the catalytic pocket on the integrase. The guanine plus adenine rich triplet repeats (GAA)n and (GGA)n appear to adopt parallel-stranded duplexes stabilized by reverse G*G and A*A non-canonical pairs, which adopt sequence-dependent distinct pairing alignments. We are currently experimentally testing a parallel-stranded DNA duplex model for self-pairing by the Friedrichs ataxia triplet repeat disease all purine (GAA)n sequence. We are well positioned to monitor both structural and energetics aspects of conformational interconversions between quadruplex folds adopted by two repeat human telomere TTAGGG and Tetrahymena telomere TTGGGG sequences, and their modulation by quadruplex-binding ligands. Parallel structure-energetics studies will be undertaken on two repeat centromeric sequences.