The Role of Metals in the Hydrolytic Cleavage of DNA and RNA

Abstract

The nucleic acids RNA and DNA consist of nucleoside building blocks joined by phosphodiester linkages. Phosphodiesters are generally inert to hydrolytic cleavage under physiological conditions because their negative charge disfavors nucleophilic attack. However, the hydrolytic scission of phosphodiester linkages is an important and common biological process, and can occur rapidly in the presence of appropriate catalysts such as ribozymes and nuclease enzymes. Metals play an important role in this process. Several possible modes of action can be invoked for metal-promoted phosphate ester hydrolysis, including Lewis acid catalysis, Br⊘nsted base catalysis by metal-bound hydroxides, nucleophilic catalysis by metal-bound hydroxides, Br⊘nsted acid catalysis by metal-bound water, and electrostatic stabilization of transition states by positively charged metal ions. Here we critically discuss the roles of metals in the hydrolytic cleavage of nucleic acids and related model substrates.