Conformation and Dynamics of Normal and Damaged DNA

Authors: Rachofsky E.L.; Ross J.B.Alexander; Osman R.

Source: Combinatorial Chemistry & High Throughput Screening, Volume 4, Number 8, December 2001 , pp. 675-706(32)

Publisher: Bentham Science Publishers

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Abstract:

The genetic information that determines the structure and function of living organisms is encoded in the nucleotide sequence of double-stranded DNA molecules. Despite an apparent structural homogeneity displayed by DNA, subtle local variations in structure and dynamics are functionally significant. Short sequences exhibit specificity for regulatory and catalytic proteins, which mediate fundamental processes necessary to the survival of the cell. However, the molecular basis for specific recognition is still incompletely understood. The “indirect readout” mechanism suggests that the relative propensity of DNA to undergo structural deformations induced by the protein contributes to specific protein-DNA recognition. Although the hypothesis was originally formulated to explain recognition of specific nucleic acid sequences by DNA-binding proteins, it may have particular application to the recognition of DNA damage, because damaged sites in DNA have different equilibrium structure and dynamics from undamaged DNA. In this work, we review the approaches that we took to investigate the questions of sequence- and damage-dependent structure and dynamics of DNA.

We describe a statistical thermodynamic model that relates DNA configurational flexibility to sequence-specific protein-DNA binding. The model provides a theoretical basis for interpreting experimental measurements of DNA dynamics. We describe results from MCSCF calculations of the excited states of 2-aminopurine (2AP), which provide the theoretical basis for the intramolecular mechanism of quenching as well as the effect of environment on this process. We then describe our investigations of the effect of stacking, base pairing, and base dynamics on the fluorescence of 2-AP in model systems, which allow us to develop the relationships between steady-state and time-resolved fluorescence parameters on the one hand and local structural and dynamic properties of DNA on the other hand. Finally, we describe the application of the experimental approach to study the conformational heterogeneity of DNA abasic sites, a commonly occurring type of DNA damage. We demonstrate the power of the experimental algorithm to characterize the physical differences between undamaged and damaged DNA, as well as the effects of nucleic acid sequence in both of these contexts. Thus, the work described herein comprises a combination of theoretical and experimental approaches to the problem of sequence- and damage-dependent DNA deformation.

Keywords: Damaged DNA; Mcscf calculation; Rna polymerase II; Time resolved fluorescence spectroscopy

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1386207013330706

Publication date: 2001-12-01

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Combinatorial Chemistry & High Throughput Screening publishes full length original research articles and reviews describing various topics in combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries) and/or high throughput screening (e.g. developmental, practical or theoretical). Ancillary subjects of key importance, such as robotics and informatics, will also be covered by the journal. In these respective subject areas, Combinatorial Chemistry & High Throughput Screening is intended to function as the most comprehensive and up-to-date medium available. The journal should be of value to individuals engaged in the process of drug discoveryand development, in the settings of industry, academia or government.

Conformation and Dynamics of Normal and Damaged DNA

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