Fig. 1: Repair pathways targeting deoxy-8-oxo-G inefficiently process the structurally equivalent ribonucleotide, 8-oxo-rG.
From: Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair
a Hydroxyl radicals (OH•) interact with and damage cellular free dGTP (2´-deoxyguanosine-5´-triphosphate) and rGTP (guanosine-5´-triphosphate) pools. Oxidation by hydroxyl radicals at C8 (green box) of dGTP and rGTP (red box) generates 8-oxo-dGTP (8-oxo-2´-deoxyguanosine-5´-triphosphate, 8dOG or Go) and 8-oxo-rGTP (8-oxo-guanosine-5´-triphosphate, 8rOG or Gro), respectively. b Scheme depicting known pathways associated with replication and repair of deoxy-8-oxo-G lesions that operate inefficiently on ribo-8-oxo-G lesions. (1) Thymine demethylation or UTP insertion, among other processes, may generate a genomic A–U base pair. The uracil can be removed by UNG (uracil DNA glycosylase, UDG) to generate a gapped repair intermediate. (2) The resulting gapped intermediate may undergo gap-filling by DNA polymerases and insertion of TTP or 8-oxo-rGTP opposite A to yield the Watson-crick (A–T) or A–Gro base pairs. Pols δ and ε are effectively unable to insert 8-oxo-rGTP and would likely not generate cytotoxic A–Gro intermediates. (3) MutYH-dependent repair of Go lesions can efficiently remove A opposite Go, however, this pathway inefficiently excises A opposite Gro and therefore likely does not participate in repair of A–Gro base pairs. (4) OGG1 can remove Go opposite C from C–Go lesions, but is inefficient in removing Gro opposite C, so this pathway is unlikely to operate in repair of C–Gro lesions. These pathways promote buildup of Gro containing lesions that are potentially more cytotoxic than Go lesions and may lead to unrepaired genomic instability.
