Site-Specific N2-dG DNA Adducts: Formation, Synthesis, and TLS Polymerase-Mediated Bypass

Abstract

The N2-position of deoxyguanosine (dG) in DNA is susceptible to modification by various damaging agents. These modifications (lesions or adducts) can stall the DNA replication by replicative polymerases, and if the common DNA repair pathways do not remove them, it can result in genomic instability. This generally leads to the death or oncogenic transformation of the cell. An important mechanism to deal with this problem is Translesion synthesis (TLS), a bypass mechanism, which involves the tolerance of DNA damage by low-fidelity DNA polymerases (TLS polymerases). To understand the accuracy of TLS polymerases, a chemical biology approach is required. In this review, we discuss the reliable methods to synthesize specific N2-dG DNA adducts and how they are tolerated by bacterial TLS polymerase Pol IV and its mammalian orthologue hpol κ. Molecular insights on the accurate bypass of these adducts emerge from the primer extension assays, X-ray crystallographic, and molecular modeling studies are reviewed here.