ABSTRACT
Cells contain extraordinarily efficient replication apparatus to duplicate their genomes during cell division. Faithfully copying the long stretches of cellular DNA demands extraordinarily high efficiency and fidelity for DNA synthesis. The replicative DNA polymerases (Pol) d and e are indeed highly efficient and accurate in copying DNA. This high efficiency and accuracy owes in part to their ability to tightly grab onto the template DNA and stringently select the correct nucleotide at the geometrically well-confined active site. The 30!50 proofreading exonuclease activity of both Pold and Pole adds another level of accuracy by removing an incorrectly incorporated nucleotide. Such a tight fit is well suited for high efficient and accurate replication from DNA templates of normal structure and chemical compositions. DNA damage such as chemical modifications of the bases would disrupt this intimate match between the replicative polymerases and the DNA template. In the presence of DNA damage, the replicative polymerases become ineffective, as they have evolved so effectively and specifically to deal with the normal DNA template. Specialized DNA polymerases are required to copy the damaged sites of the DNA template. The challenge for these specialized polymerases is not high efficiency and accuracy, but merely being able to copy the damaged sites. Consequently, these polymerases had evolved to possess very different biochemical properties as compared to the replicative polymerases.
