"Action-at-a-distance" mutagenesis - 8-oxo-7,8-dihydro-2 '-deoxyguanosine causes base substitution errors at neighboring template sites when copied by DNA polymerase beta

8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), a common oxidative DNA lesi on, favors a syn-conformation in DNA, enabling formation of stable 8-oxo-dG A base mispairs resulting in G.C --> T.A transversion mutations. When huma n DNA polymerase (pol) beta was used to copy a short single-stranded gap co ntaining a site-directed 8-oxo-dG lesion, incorporation of dAMP opposite 8- oxo-dG was slightly favored over dCMP depending on "downstream" sequence co ntext. Unexpectedly, however, a significant increase in dCMP A and dGMP A m ispairs was also observed at the "upstream" 3'-template site adjacent to th e lesion. Errors at these undamaged template sites occurred in four sequenc e contexts with both gapped and primed single-stranded DNA templates, but n ot when pol alpha replaced pol beta. Error rates at sites adjacent to 8-oxo -dG were roughly 1% of the values opposite 8-oxo-dG:, potentially generatin g tandem mutations during in vivo short-gap repair synthesis by pol beta, W hen 8-oxo-dG was replaced with 8-bromo-2'-deoxyguanosine, incorporation of dCMP was strongly favored by both enzymes, with no detectable misincorporat ion occurring at neighboring template sites.