DNA Polymerases and Oxidative Damage: Friends or Foes?

A.      Amoroso; E.      Crespan; U.      Wimmer; U.      Hubscher; G.      Maga

Abstract

DNA is modified by many mutagens, including reactive oxygen species (ROS). When ROS react with DNA, various kinds of modified base and/or sugar moieties are produced. One of the most important oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxo-G). Contrary to normal deoxyguanosine, 8-oxo-G favors a syn conformation, enabling it to form a Hoogsteen base pair with adenine which resembles a normal Watson-Crick base pair in shape and geometry. As a consequence, most human DNA polymerases (pols) studied so far show significant error-prone bypass of 8-oxo-G. The 1,2-dihydro-2-oxoadenine (2-OH-A) is another common DNA lesion produced by ROS. 2-OH-A possesses significant mutagenic potential in living cells. When challenged with a 2-OH-A lesion on the template, DNA pols often misinsert G and C nucleotides, with various efficiencies depending upon the sequence context. We have recently shown that human DNA pol λ is extremely efficient in performing error-free bypass of both 8-oxo-G and 2-OH-A lesions, and that its efficiency is positively modulated by the auxiliary factors proliferating cell nuclear antigen and replication protein A. In this review we will summarize the most recent advancements in the field of oxidative DNA damage tolerance with special emphasis on the pro- and anti-mutagenic roles of DNA pols and auxiliary proteins.