Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

• Published in: Oncogene Vol. 18; no. 28; pp. 4047 - 4054
• Main Authors: CHATURVEDI, P, ENG, W. K, SCOTT, G. F, XIAOTONG LI, CARR, S. A, JOHNSON, R. K, WINKLER, J. D, ZHOU, B.-B. S, YUAN ZHU, MATTERN, M. R, MISHRA, R, HURLE, M. R, XIAOLONG ZHANG, ANNAN, R. S, QUINN LU, FAUCETTE, L. F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 15-07-1999; Nature Publishing Group
• Subjects: Alkylating Agents - pharmacology; Animals; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell cycle; Cell Cycle - genetics; Cell Cycle Proteins - metabolism; Cell cycle, cell proliferation; Cell physiology; Cells, Cultured; Checkpoint Kinase 2; CHK1 protein; CHK2 protein; Cloning, Molecular; Complementation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Repair - genetics; DNA, Complementary - genetics; DNA, Fungal - drug effects; DNA, Fungal - genetics; DNA, Fungal - radiation effects; DNA-Binding Proteins; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungal Proteins - physiology; Gamma Rays; Genetic Complementation Test; Humans; Hydroxyurea; Hydroxyurea - pharmacology; Mammals; Mass spectroscopy; Molecular and cellular biology; Phosphorylation; Protein Kinases; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - physiology; Proteins - physiology; ras-GRF1; Rats; Replication; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - radiation effects; Schizosaccharomyces - drug effects; Schizosaccharomyces - genetics; Schizosaccharomyces - radiation effects; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins; Signal Transduction; Species Specificity; Topoisomerase I Inhibitors; Topotecan; Topotecan - pharmacology; Transcription; Tumor Suppressor Proteins; Yeast; γ Radiation; Skin disease; Phosphorylation; Rat; Cardiovascular disease; Homology; Vascular disease; Signal transduction; Regulation(control); Cell cycle; Tumor suppressor gene; Human; Immunopathology; Nervous system diseases; Nucleotide sequence; Enzyme; Transferases; Rodentia; Genetic disease; Eye disease; Vertebrata; Mammalia; Shutdown; Protein kinase; DNA; Ataxia telangiectasia; Lesion
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202925

In response to DNA damage and replication blocks, cells activate pathways that arrest the cell cycle and induce the transcription of genes that facilitate repair. In mammals, ATM (ataxia telangiectasia mutated) kinase together with other checkpoint kinases are important components in this response. We have cloned the rat and human homologs of Saccharomyces cerevisiae Rad 53 and Schizosaccharomyces pombe Cds1, called checkpoint kinase 2 (chk2). Complementation studies suggest that Chk2 can partially replace the function of the defective checkpoint kinase in the Cds1 deficient yeast strain. Chk2 was phosphorylated and activated in response to DNA damage in an ATM dependent manner. Its activation in response to replication blocks by hydroxyurea (HU) treatment, however, was independent of ATM. Using mass spectrometry, we found that, similar to Chk1, Chk2 can phosphorylate serine 216 in Cdc25C, a site known to be involved in negative regulation of Cdc25C. These results suggest that Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Activation of Chk2 might not only delay mitotic entry, but also increase the capacity of cultured cells to survive after treatment with gamma-radiation or with the topoisomerase-I inhibitor topotecan.