Abstract
Incorporation of mismatched nucleotides during DNA replication or repair leads to transition or transversion mutations and is considered as a predominant source of base substitution mutagenesis in cancer cells. Watson-Crick like dG:dT base pairing is considered to be an important source of genome instability. Here we show that DNA polymerase (pol) μ insertion of 7,8-dihydro-8′-oxo-dGTP (8-oxodGTP) or deoxyguanosine triphosphate (dGTP) into a model double-strand break DNA repair substrate with template base T results in efficient ligation by DNA ligase. These results indicate that pol μ-mediated dGTP mismatch insertion opposite template base T coupled with ligation could be a feature of mutation prone nonhomologous end joining during double-strand break repair.
Highlights
Incorporation of mismatched nucleotides during DNA replication or repair leads to transition or transversion mutations and is considered as a predominant source of base substitution mutagenesis in cancer cells
We show that DNA ligase efficiently ligates the nonhomologous end joining (NHEJ) repair intermediate following insertion of Watson-Crick like mismatches deoxyguanosine triphosphate (dGTP) or 8-oxodGTP opposite template base T by pol μ in vitro
We investigated the impact of two Watson-Crick like promutagenic mismatches on the downstream steps during DNA repair
Summary
Incorporation of mismatched nucleotides during DNA replication or repair leads to transition or transversion mutations and is considered as a predominant source of base substitution mutagenesis in cancer cells. We show that DNA ligase efficiently ligates the NHEJ repair intermediate following insertion of Watson-Crick like mismatches dGTP or 8-oxodGTP opposite template base T by pol μ in vitro. Comparison of 8-oxodGTP:dT insertion coupled with ligation In contrast to this picture with pol μ, we observed ligation failure after 8-oxodGMP insertion opposite template base T by the other X-family repair DNA polymerases pol β and pol λ (Supplementary Fig. 7). This indicates that these pols were not able to accommodate the wobble or Watson-Crick like dG:dT mismatch in a fashion that enables DNA ligase action, as seen with pol μ. We previously demonstrated that 8-oxodGMP insertion by pol β or pol λ opposite bases C or A confounds DNA ligation during BER11
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