Inactivation by oxidation and recruitment into stress granules of hOGG1 but not APE1 in human cells exposed to sub-lethal concentrations of cadmium.
The induction of mutations in mammalian cells exposed to cadmium has been associated with the oxidative stress triggered by the metal. There is increasing evidence that the mutagenic potential of Cd is not restricted to the induction of DNA lesions. Cd has been shown to inactivate several DNA repair enzymes. Here we show that exposure of human cells to sub-lethal concentrations of Cd leads to a time- and concentration-dependent decrease in hOGG1 activity, the major DNA glycosylase activity responsible for the initiation of the base excision repair (BER) of 8-oxoguanine, an abundant and mutagenic form of oxidized guanine. Although there is a slight effect on the level of hOGG1 transcripts, we show that the inhibition of the 8-oxoguanine DNA glycosylase activity is mainly associated with an oxidation of the hOGG1 protein and its disappearance from the soluble fraction of total cell extracts. Confocal microscopy analyses show that in cells exposed to Cd hOGG1-GFP is recruited to discrete structures in the cytoplasm. These structures were identified as stress granules. Removal of Cd from the medium allows the recovery of the DNA glycosylase activity and the presence of hOGG1 in a soluble form. In contrast to hOGG1, we show here that exposure to Cd does not affect the activity of the second enzyme of the pathway, the major AP endonuclease APE1.
CEA, Institut de Radiobiologie Cellulaire et Moléculaire, 18 route du Panorama, F-92265 Fontenay aux Roses, France.
Anne
A
Bravard
Anna
A
Campalans
Monique
M
Vacher
Barbara
B
Gouget
Céline
C
Levalois
Sylvie
S
Chevillard
J Pablo
JP
Radicella
D002104:Cadmium / Q000633:toxicity*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D045647:DNA Glycosylases / Q000187:drug effects* / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000187:drug effects*; D015536:Down-Regulation; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012323:RNA Processing, Post-Transcriptional
D002104:Cadmium; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase