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Magnesium NMR of DNA Repair Proteins

Paul Ellis, Principal Investigator

Funding Agency: National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering

The chemistry of water activated by a magnesium ion is central to the function of the DNA repair proteins, apurinic/apyrimidic endonuclease 1 (Ape1) and polymerase A (Pol A). These proteins are key constituents of the base excision repair (BER) pathway, a process that plays a critical role in preventing the cytotoxic and mutagenic effects of most spontaneous, alkylation, and oxidative DNA damage. The Magnesium NMR of DNA Repair Proteins research team at Pacific Northwest National Laboratory (PNNL) is applying a novel method using low temperature (10K) solid-state 25Mg NMR to study DNA repair proteins and their model systems. Their goal is to establish a relationship between 25Mg magnetic resonance parameters (e.g., quadrupole coupling constants, shielding tensors, and their relative orientations) and the structure-function relationships for known magnesium-dependent DNA repair proteins and to extrapolate those relationships to other magnesium-dependent DNA repair proteins in which the role of the metal is less defined. These experiments are being performed in concert with ab initio electronic structure calculations. The combination of these two methods provides a firm basis to understand the chemical role of these metals in their respective proteins. Additionally, triple resonance experiments (1H, [15N or 31P], 25Mg) are being performed to identify neighboring ligands and to determine selective distances between the magnesium and the substrates. The results of these experiments are critical to gain a mechanistic understanding of the role magnesium plays in these critical DNA repair proteins.

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