The Role of RNA and [4Fe/4S]2+/+ Iron Sulfur Clusters in the Biosynthesis of Deoxyribonucleotides


Haley Hill

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The "RNA World Hypothesis" is the most prevalent theory describing the origins of life and postulates that RNA preceded DNA and proteins in the prebiotic milieu. This theory draws from the knowledge that RNA is capable of carrying the genetic code and of limited catalytic function, thus incorporating the functions of both DNA and proteins. We propose that RNA-based enzymes (ribozymes) catalyzed the early synthesis of DNA nucleotides using small peptides and metal cofactors. Redox-active cofactors such as iron-sulfur clusters have recently been shown to self-assemble in coordination with short peptides. Beginning with a 16mer peptide that assembles a [4Fe/4S]2+/+ cluster, we have designed two peptides, one that incorporates a biotin group and one with a lysine-tryptophan-lysine (KWK) DNA intercalation motif. Both modified peptides were shown to assemble [4Fe/4S]2+/+ clusters under anaerobic conditions according to UV-Visible spectroscopy and EPR data. By tethering the biotinylated peptide to an agarose-strepavidin column, we will select an RNA molecule(s) from a large combinatorial pool that is capable of binding to the immobilized peptide-[4Fe/4S]2+/+ complex. Concurrently, we are probing the electrochemistry of the KWK-peptide-iron-sulfur complex upon intercalation with a 15-nucleotide DNA duplex anchored to a gold electrode. These studies may provide insight into the existence of metal-binding RNA molecules capable of generating the basic building blocks of DNA, thus providing a link between the ancient RNA world and modern living organisms.


M. Hill




Support provided by:The Arnold and Mabel Beckman Scholars Award

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