Action-at-a-distance mutations by 8-oxo-7,8-dihydroguanine: adenine pair triggered by MUTYH

8-Oxo-7,8-dihydroguanine (8-hydroxyguanine, G^O) is a major damaged base caused by oxidation. Misincorporation of dATP opposite G^O by DNA polymerases leads to a G:C→T:A transversion at the damaged site via G^O:A intermediate formation. The G^O:A pair is also formed by 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate incorporation opposite A. The G^O:C and G^O:A pairs are both repaired through the base excision repair (BER) pathway to suppress the G:C→T:A mutations. G^O:C also induces action-at-a-distance mutations around the damaged base. These untargeted mutations seem to be induced through the excision of G^O from G^O:C by DNA glycosylases, such as OGG1 and NEIL1, in the BER pathway. The adenine base of G^O:A is excised by a specific adenine DNA glycosylase, MUTYH, and this excision potentially induces action-at-a-distance mutations.

In this study, plasmid DNA bearing a G^O:A pair was introduced into human U2OS cells to investigate the untargeted mutations by the G^O:A pair. The G^O:A pair induced action-at-a-distance mutations at C bases in 5'-TpC-3' of the G^O-strand, in contrast to those by G^O:C, which elicit mutations at G bases of 5'-GpA-3'. Furthermore, the untargeted mutations were suppressed by the MUTYH knockdown.

The G^O:A pair induced the action-at-a-distance mutations through base excision by the MUTYH glycosylase.