DNA Hydrolysis: Mechanism and Reactivity

It is essential that the primary, linear structure of DNA is stable to preserve the sequence of bases and hence the genetic code. The bases are assembled as nucleotide units, joined together by phosphate diester links. Given the need to permanently retain genetic information, it is not surprising that the phosphate diester is far more kinetically stable than other common biological functional groups such as amides or esters (Westheimer 1987). However, the backbone must also be cleavable to facilitate the synthesis, manipulation and repair of DNA. This role is naturally carried out by nucleases, which catalyse the cleavage of DNA either by hydrolysis of the phosphate diester bond (with varying degrees of sequence specificity) or by catalysing elimination of phosphate (and destroying one of the nucleotide units). The purpose of this brief review is to summarise the mechanisms relevant to DNA hydrolysis and in particular to estimate the rate of hydrolysis through attack at the phosphate diester under mild, aqueous conditions.