Metallothionein-III prevents gamma-ray-induced 8-oxoguanine accumulation in normal and hOGG1-depleted cells

J Biol Chem. 2004 Aug 13;279(33):34138-49. doi: 10.1074/jbc.M402530200. Epub 2004 Jun 8.

Abstract

Metallothioneins (MT) play an important biological role in preventing oxidative damage to cells. We have previously demonstrated that the efficiency of the protective effect of MT-III against the DNA degradation from oxidative damage was much higher than that of MT-I/II. As an extension of the latter investigation, this study aimed to assess the ability of MT-III to suppress 8-oxoguanine (8-oxoG), which is one of the major base lesions formed after an oxidative attack to DNA and the mutant frequency of the HPRT gene in human fibroblast GM00637 cells upon exposure to gamma-rays. We found that human MT-III expression decreased the level of 8-oxoG and mutation frequency in the gamma-irradiated cells. Using an 8-oxoguanine DNA glycosylase (OGG1)-specific siRNAs, we also found that MT-III expression resulted in the suppression of the gamma-radiation-induced 8-oxoG accumulation and mutation in the OGG1-depleted cells. Moreover, the down-regulation of MT in human neuroblastoma SKNSH cells induced by MT-specific siRNA led to a significant increase in the 8-oxoG level, after exposure to gamma-irradiation. These results suggest that under the conditions of gamma-ray oxidative stress, MT-III prevents the gamma-radiation-induced 8-oxoG accumulation and mutation in normal and hOGG1-depleted cells, and this suppression might, at least in part, contribute to the anticarcinogenic and neuroprotective role of MT-III.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / chemistry
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Blotting, Western
  • Cell Line
  • DNA / metabolism
  • DNA Damage
  • DNA Glycosylases / metabolism*
  • DNA Mutational Analysis
  • DNA-Formamidopyrimidine Glycosylase / chemistry
  • Dose-Response Relationship, Radiation
  • Down-Regulation
  • Fibroblasts / metabolism
  • Gamma Rays
  • Gene Silencing
  • Genetic Vectors
  • Guanine / analogs & derivatives*
  • Guanine / chemistry*
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Mutation
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism
  • Oxidative Stress
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Antioxidants
  • Nerve Tissue Proteins
  • Protein Isoforms
  • RNA, Messenger
  • RNA, Small Interfering
  • growth inhibitory factor
  • 8-hydroxyguanine
  • Guanine
  • DNA
  • L-Lactate Dehydrogenase
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human
  • DNA-Formamidopyrimidine Glycosylase