DNA polymerases involved in the incorporation of oxidized nucleotides into DNA: their efficiency and template base preference.

摘要

Genetic information must be duplicated with precision and accurately passed on to daughter cells and later generations. In order to achieve this goal, DNA polymerases (Pols) have to faithfully execute DNA synthesis during chromosome replication and repair. However, the conditions under which Pols synthesize DNA are not always optimal; the template DNA can be damaged by various endogenous and exogenous genotoxic agents including reactive oxygen species (ROS), and ROS oxidize dNTPs in the nucleotide pool from which Pols elongate DNA strands. Both damaged DNA and oxidized dNTPs interfere with faithful DNA synthesis by Pols, inducing various cellular abnormalities, such as mutations, cancer, neurological diseases, and cellular senescence. In this review, we focus on the process by which Pols incorporate oxidized dNTPs into DNA and compare the properties of Pols: efficiency, i.e., k(cat)/K(m), k(pol)/K(d) or V(max)/K(m), and template base preference for the incorporation of 8-oxo-dGTP, an oxidized form of dGTP. In general, Pols involved in chromosome replication, the A- and B-family Pols, are resistant to the incorporation of 8-oxo-dGTP, whereas Pols involved in repair and/or translesion synthesis, the X- and Y-family Pols, incorporate nucleotides in a relatively efficient manner and tend to incorporate it opposite template dA rather than template dC, though there are several exceptions. We discuss the molecular mechanisms by which Pols exhibit different template base preferences for the incorporation of 8-oxo-dGTP and how Pols are involved in the induction of mutations via the incorporation of oxidized nucleotides under oxidative stress.