title: Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage.
abstract: Neuronal death in the central nervous system contributes to the development of age-related neurodegeneration. The ATR/Chk1 pathway appears to function neuroprotectively to prevent DNA damage induced by cytotoxic agents. Here, we examine the function of Chk1 on cell viability of cortical neurons in the absence of additional DNA damaging stimuli. The Chk1-specific inhibitor, UCN-01, and the ATR inhibitor, Caffeine, cause neuronal apoptosis in differentiated neurons in the absence of additional treatment, whereas inhibition of ATM or Chk2, does not. UCN-01 treatment increased the detection of γ-H2AX phosphorylation, DNA strand breaks, and an activated p53-dependent DNA damage response (DDR), suggesting that Chk1 normally helps to maintain genomic stability. UCN-01 treatment also enhanced the apoptosis seen in neurons treated with DNA damaging agents, such as camptothecin (CPT). Our results indicate that Chk1 is essential for neuronal survival, and perturbation of this pathway increases a cell's sensitivity to naturally accumulating DNA damage.
authors.affiliation: Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, 12003, USA.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ye
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Blain
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D002454:Cell Differentiation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005260:Female; D016158:Genes, p53; D042822:Genomic Instability; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C576887:ataxia telangiectasia and Rad3-related kinase, rat; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D002166:Camptothecin