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

## TL;DR

This study shows that the DNA repair enzyme MUTYH causes mutations far from the original DNA damage site when repairing a specific DNA base pair.

## Contribution

The study reveals that MUTYH-induced action-at-a-distance mutations occur at C bases in a specific DNA sequence context.

## Key findings

- GO:A pairs induce action-at-a-distance mutations at C bases in 5'-TpC-3' sequences.
- MUTYH knockdown suppresses these untargeted mutations.
- GO:A and GO:C pairs cause mutations at different DNA sequence contexts.

## Abstract

8-Oxo-7,8-dihydroguanine (8-hydroxyguanine, GO) is a major damaged base caused by oxidation. Misincorporation of dATP opposite GO by DNA polymerases leads to a G:C→T:A transversion at the damaged site via GO:A intermediate formation. The GO:A pair is also formed by 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate incorporation opposite A. The GO:C and GO:A pairs are both repaired through the base excision repair (BER) pathway to suppress the G:C→T:A mutations. GO:C also induces action-at-a-distance mutations around the damaged base. These untargeted mutations seem to be induced through the excision of GO from GO:C by DNA glycosylases, such as OGG1 and NEIL1, in the BER pathway. The adenine base of GO: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 GO:A pair was introduced into human U2OS cells to investigate the untargeted mutations by the GO:A pair. The GO:A pair induced action-at-a-distance mutations at C bases in 5'-TpC-3' of the GO-strand, in contrast to those by GO:C, which elicit mutations at G bases of 5'-GpA-3'. Furthermore, the untargeted mutations were suppressed by the MUTYH knockdown.

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

The online version contains supplementary material available at 10.1186/s41021-025-00340-0.