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

William A. Cliby, Christopher J. Roberts, Karlene A. Cimprich, Cheri M. Stringer, John R. Lamb, Stuart L. Schreiber, Stephen H. Friend

Research output: Contribution to journalArticle

461 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalEMBO Journal
Volume17
Issue number1
DOIs
StatePublished - Jan 2 1998

Keywords

  • ATR protein
  • Cell cycle checkpoint
  • DNA damage
  • Hyroxyurea
  • Ionizing radiation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Cliby, W. A., Roberts, C. J., Cimprich, K. A., Stringer, C. M., Lamb, J. R., Schreiber, S. L., & Friend, S. H. (1998). Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO Journal, 17(1), 159-169. https://doi.org/10.1093/emboj/17.1.159