Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints

• Published in: The EMBO journal Vol. 17; no. 1; pp. 159 - 169
• Main Authors: Cliby, William A., Roberts, Christopher J., Cimprich, Karlene A., Stringer, Cheri M., Lamb, John R., Schreiber, Stuart L., Friend, Stephen H.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 02.01.1998
• Subjects: Ataxia Telangiectasia Mutated Proteins; ATR protein; Cell Cycle; cell cycle checkpoint; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Transformed; DNA Damage; DNA Repair; DNA Replication; Fibroblasts - drug effects; Fibroblasts - radiation effects; G2 Phase - radiation effects; Humans; hydroxyurea; ionizing radiation; Mitosis - radiation effects; Phenotype; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases; Radiation Tolerance
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/17.1.159

ATR, a phosphatidylinositol kinase‐related protein homologous to ataxia telangiectasia mutated (ATM), is important for the survival of human cells following many forms of DNA damage. Expression of a kinase‐inactive allele of ATR (ATRkd) in human fibroblasts causes increased sensitivity to ionizing radiation (IR), cis‐platinum and methyl methanesulfonate, but only slight UV radiation sensitivity. ATRkd overexpression abrogates the G2/M arrest after exposure to IR, and overexpression of wild‐type ATR complements the radioresistant DNA synthesis phenotype of cells lacking ATM, suggesting a potential functional overlap between these proteins. ATRkd overexpression also causes increased sensitivity to hydroxyurea that is associated with microtubule‐mediated nuclear abnormalities. These observations are consistent with uncoupling of certain mitotic events from the completion of S‐phase. Thus, ATR is an important component of multiple DNA damage response pathways and may be involved in the DNA replication (S/M) checkpoint.