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

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

Research output: Contribution to journalArticle

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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 G 2/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

Fingerprint

Ataxia Telangiectasia
Cell Cycle Checkpoints
Ionizing Radiation
DNA Damage
Phosphotransferases
Cells
Methyl Methanesulfonate
Defects
Hydroxyurea
Radiation Tolerance
DNA
Ionizing radiation
Phosphatidylinositols
DNA Replication
S Phase
Microtubules
Protein Kinases
Cisplatin
Cell Survival
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

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

Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. / Cliby, William Arthur; Roberts, Christopher J.; Cimprich, Karlene A.; Stringer, Cheri M.; Lamb, John R.; Schreiber, Stuart L.; Friend, Stephen H.

In: EMBO Journal, Vol. 17, No. 1, 02.01.1998, p. 159-169.

Research output: Contribution to journalArticle

Cliby, William Arthur ; Roberts, Christopher J. ; Cimprich, Karlene A. ; Stringer, Cheri M. ; Lamb, John R. ; Schreiber, Stuart L. ; Friend, Stephen H. / Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. In: EMBO Journal. 1998 ; Vol. 17, No. 1. pp. 159-169.
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