FIGURE 2.

The human GO repair system. (A) 8-oxoG lesion is among the most common forms of oxidative DNA damage, which can arise following exposure to endogenous and/or exogenous ROS. (B) An 8-oxoG:C base pair is recognized and excised by the OGG1 glycosylase, producing an apurinic (AP) site, which is cleaved by APE1, and then processed by downstream BER to restore the correct G:C base pair. If 8-oxoG escapes repair it can miscode for adenine upon DNA replication. MUTYH glycosylase recognizes a 8-oxoG:A mispair and excises the undamaged adenine, thereby initiating long-patch BER to restore the 8-oxoG:C base pair. This allows OGG1 another chance to excise 8-oxoG and to initiate BER to restore the G:C base pair. If the 8-oxoG:A mispair is not repaired, a further round of replication converts the damage to a G:C to T:A transversion mutation. Lesion processing by BER generates repair intermediates, including AP sites and SSBs, which can cause replication fork collapse and subsequent DSBs. (C) MTH1 sanitase provides further protection against 8-oxoG mutagenesis through removing 8-oxodGTP from the nucleotide pool by hydrolyzing it to 8-oxodGMP and pyrophosphate. This prevents misincorporation of 8-oxodGTP opposite a template adenine during DNA replication or repair. The mismatch repair (MMR) enzymes (not shown) can also eliminate 8-oxoG from newly synthesized DNA that has been misinserted opposite adenine. (Black arrows: canonical repair steps. Brown arrows: Rounds of replication. Dashed arrows: mutagenesis or DNA damage generating steps).