Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts.
Even though epidemiological studies have identified arsenic compounds as carcinogenic to humans, they are not mutagenic in bacterial and mammalian test systems. However, they increase the mutagenicity and clastogenicity in combination with other DNA damaging agents and there are indications of inhibition of DNA repair processes. We investigated the effect of arsenic(III) on nucleotide excision repair (NER) after UV irradiation in human fibroblasts in detail by using two repair-proficient and one partly repair-deficient xeroderma pigmentosum group C human fibroblast cell lines. The results show that two steps of NER are affected by arsenite. Most severely, the incision frequency is reduced at concentrations as low as 2.5 microM arsenic(III); at higher, cytotoxic concentrations, the ligation of repair patches is also impaired. Furthermore, our results indicate that both the global genome repair pathway and the transcription-coupled repair pathway are affected by arsenite. Repair inhibition may well explain the potentiation of genotoxic effects by arsenic in combination with other DNA damaging agents and may thus be of high relevance for the carcinogenic action of arsenic compounds.
Hartwig
A
A
University of Bremen, Department of Biology and Chemistry, Germany.
Groblinghoff
U D
UD
Beyersmann
D
D
Natarajan
A T
AT
Filon
R
R
Mullenders
L H
LH
D018053:Arsenites / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
D018053:Arsenites; D013723:Teratogens; C015001:arsenite