NEIL1: the second DNA glycosylase involved in action-at-a-distance mutations induced by 8-oxo-7,8-dihydroguanine.

Abstract

8-Oxo-7,8-dihydroguanine (G^O, 8-hydroxyguanine), an oxidatively damaged base, induces mutations and is involved in cancer initiation. In addition to G:C→T:A transversions at the damaged site, it causes untargeted base substitution (action-at-a-distance) mutations at the G bases of 5'-GpA-3' sites in human cells. Paradoxically, OGG1, a DNA glycosylase involved in the base excision repair (BER) pathway, enhances the action-at-a-distance mutations by G^O. In this study, other DNA glycosylases, potential repair enzymes for the G^O base, were knocked down, and their effects on the untargeted mutations were examined using the supF reporter gene. The knockdown of NEIL1 decreased such mutations, while those of NTH1, NEIL2, and NEIL3 had no effects. The double knockdown of OGG1 and NEIL1 additively affected the mutation frequency. These results indicated that NEIL1 is another BER protein involved in the action-at-a-distance mutations triggered by the oxidized guanine base.