Genetic predisposition to the cytotoxicity of arsenic: the role of DNA damage and ATM.
Arsenic is a pervasive cytotoxin and carcinogen in the environment. Although its mode of action has yet to be fully elucidated, oxidative DNA damage has been suggested. A series of DNA repair-defective human and hamster cell lines associated with sensitivity to oxidative agents were examined for their response to arsenic-induced cytotoxicity. Only the Ataxia telangiectasia (AT) cells displayed a marked hypersensitive response (greater than twofold). The protective role of the ATM protein was confirmed by the normal response to arsenic displayed by AT cells expressing wild-type ATM. Although the ATM protein plays a pivotal role in response to DNA double-strand breakage, none of the other cell lines with defects in double-strand break repair displayed a similar hypersensitivity. Further examination indicated that concentrations of sodium arsenite as high as 1 mg/l do not generate significant levels of double-strand breaks. Our data suggest that the ATM protein functions in an important but different capacity in the cellular response to arsenic toxicity than it does in response to agents that generate double-strand breaks, such as ionizing radiation. Furthermore, the lack of hypersensitivity to arsenic displayed by the other cell lines calls into question the hypothesis that DNA damage is a significant factor in arsenic cytotoxicity.
Mei
Nan
N
Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
Lee
Jane
J
Sun
Xuejun
X
Xing
James Z
JZ
Hanson
John
J
Le
X Chris
XC
Weinfeld
Michael
M
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D016466:CHO Cells; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D017670:Sodium Compounds / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018053:Arsenites; D002273:Carcinogens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C017947:sodium arsenite; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases