8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1

Free Radic Biol Med. 2013 Aug;61:384-94. doi: 10.1016/j.freeradbiomed.2013.04.011. Epub 2013 Apr 21.

Abstract

8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant DNA base lesions induced by reactive oxygen species (ROS). Accumulation of 8-oxoG in the mammalian genome is considered a marker of oxidative stress, to be causally linked to inflammation, and is thought to contribute to aging processes and various aging-related diseases. Unexpectedly, mice that lack 8-oxoguanine DNA glycosylase-1 (OGG1) activity and accumulate 8-oxoG in their genome have a normal phenotype and longevity; in fact, they show increased resistance to both inflammation and oxidative stress. OGG1 excises and generates free 8-oxoG base during DNA base-excision repair (BER) processes. In the present study, we report that in the presence of the 8-oxoG base, OGG1 physically interacts with guanine nucleotide-free and GDP-bound Rac1 protein. This interaction results in rapid GDP→GTP, but not GTP→GDP, exchange in vitro. Importantly, a rise in the intracellular 8-oxoG base levels increases the proportion of GTP-bound Rac1. In turn Rac1-GTP mediates an increase in ROS levels via nuclear membrane-associated NADPH oxidase type 4. These results show a novel mechanism by which OGG1 in complex with 8-oxoG is linked to redox signaling and cellular responses.

Keywords: 8-Oxoguanine; 8-Oxoguanine DNA glycosylase-1; Rac1 GTPase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Glycosylases / physiology*
  • DNA Repair*
  • Female
  • Guanine / analogs & derivatives
  • Guanine / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • NADPH Oxidase 4
  • NADPH Oxidases / analysis
  • Neuropeptides / analysis
  • Neuropeptides / physiology*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • rac1 GTP-Binding Protein / analysis
  • rac1 GTP-Binding Protein / physiology*

Substances

  • Neuropeptides
  • Rac1 protein, mouse
  • Reactive Oxygen Species
  • 8-hydroxyguanine
  • Guanine
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • DNA Glycosylases
  • Ogg1 protein, mouse
  • rac1 GTP-Binding Protein