ATR regulates hexavalent chromium-induced S-phase checkpoint through phosphorylation of SMC1.
Hexavalent chromium (Cr[VI]) is an industrial waste product known to cause nasal and lung cancer in exposed workers. Intracellularly, Cr[VI] undergoes a series of enzymatic reductions resulting in the formation of reactive chromate intermediates and oxygen free radicals. These metabolites react with DNA to cause numerous types of genomic lesions, but the cellular response to these genotoxic insults is poorly understood. Recently, we demonstrated that in response to DNA damage induced by Cr[VI], an ataxia-telangiectasia mutated (ATM) and structural maintenance of chromosomal protein 1 (SMC1)-dependent S-phase checkpoint is activated. Interestingly, this checkpoint response was only ATM-dependent in cells exposed to low doses of Cr[VI], we demonstrate that the ATM and Rad3 related kinase, ATR, is required to activate the S-phase checkpoint. In response to all doses of Cr[VI], ATR is activated and phosphorylates SMC1 to facilitate the checkpoint. Further, chromatin binding ability of Rad17 is required for this process. Taken together, these results indicate that the Rad17-ATR-SMC1 pathway is essential for Cr[VI]-induced S-phase checkpoint activation.
Wakeman
Timothy P
TP
Department of Genetics and Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA 70112, United States.
Xu
Bo
B
D064007:Ataxia Telangiectasia Mutated Proteins; D002274:Carcinogens, Environmental / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D002857:Chromium / Q000494:pharmacology*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004586:Electrophoresis / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D002274:Carcinogens, Environmental; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D002857:Chromium; C074702:chromium hexavalent ion; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases