Dr. Jens Volker: Dynamic DNA Energy Landscapes: Implications and Speculations

Dr. Jens Volker

Genomic DNA is far more polymorphic than the singular, static double helical repository of genetic information often depicted in textbooks. This polymorphism has significant functional consequences. In fact, DNA is a highly dynamic polymer that can undergo local conformational transitions, deletion, and expansion events in response to endogenous and exogenous stimuli. Intriguingly, the propensity to undergo dynamic rearrangements appears, in part, to be encoded In the DNA sequence itself. Such dynamic alterations can have profound consequences for the biological function of nucleic acids, including, but not limited to gene regulation and dysregulation, as well as the development of various genomically-triggered disease states. A good example of the later is the spontaneous, length-dependent expansion of CNG trinucleotide repeats. Such expansions can ultimately lead to either age-dependent or heritable, debilitating genetic diseases in human carriers of repeat domains prone to expansion, which aptly has been referred to as “dynamic mutations from dynamic DNA states”.  Using custom designed oligonucleotide model systems and applying a variety of calorimetric and spectroscopic tools (UV, CD, fluorescence), we have characterized the forces that control the complex dynamic behaviors of such sequences and the biological processes that contribute to expansion events. Our study design is based on the Aufbau principle: namely, we start by characterizing the simple, often static, model system, which serves as a reference state, and then probe ever more complex dynamic systems that resemble what is perceived to be relevant to biology functions. From these results we construct energy profiles and energy landscapes that map the relationships between different dynamic states. Such thermodynamic and kinetic mappings allow us to begin to interpret our macroscopic results in terms of microscopic mechanisms. In the aggregate, our studies are beginning to shed light on the hidden levels of complexity imposed by the dynamics of such repeat domains on DNA structure and function.