ABSTRACT
The need to transmit genetic information from parent to daughter cells in a precise manner is fulfilled by high-fidelity DNA replication. The main components in this machinery are high-fidelity replicative DNA polymerases. The high precision of these replication machines is achieved by a tight fit into the active site of the Watson-Crick A:T and G:C base pairs, along with specific hydrogen bonds and other stabilizing interactions, and a 30!50 exonuclease proofreading activity (1-3). This high-precision and finely tuned mechanism of action of replicative DNA polymerases leads to inhibition of DNA synthesis upon encounter with lesions in DNA, whose chemistry and architecture strongly deviate from that of the four canonical nucleotides. These modified template nucleotides cannot be accommodated in the active site of replicative DNA polymerases, or else they cause structural or conformational changes that greatly reduce the catalytic efficiency and/or fidelity of the polymerase (4-6). Why are there DNA lesions left in DNA despite the presence and operation of multiple DNA repair mechanisms that act before replication commences? The two simplest reasons are (1) DNA repair mechanisms, like any other biological mechanism, are not 100% efficient and (2) some lesions may form in DNA during replication.
