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

Oncogene volume 18, pages 4047–4054 (1999)Cite this article

Abstract

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 γ-radiation or with the topoisomerase-I inhibitor topotecan.

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Acknowledgements

We thank Jeff Jackson and Amy Roshak for discussion and suggestions during the course of this work, John D Martin for peptide synthesis, Mike Hansbury for technical help, Jackson Wong and Doug Fecteau for assistance in tissue culture work. We thank Kristi Forbes, Hiroto Okayama and Paul Russell for providing S. pombe Cds1 constructs ΔCds1 strains. P Chaturvedi is a postdoctoral fellow supported by National Cancer Institute grant (CA-50771-09).

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Authors and Affiliations

  1. Department of Oncology Research, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Priya Chaturvedi, Wai K Eng, Michael R Mattern, Rubin Mishra, Leo F Faucette, Randall K Johnson, James D Winkler & Bin-Bing S Zhou

  2. Department of Molecular Biology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Yuan Zhu & Xiaotong Li

  3. Department of Bioinformatics, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Mark R Hurle

  4. Department of Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Xiaolong Zhang, Roland S Annan & Steven A Carr

  5. Department of Gene Expression Sciences, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Quinn Lu

  6. Department of Protein Biochemistry, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, Pennsylvania, USA

    Gilbert F Scott

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  1. Priya Chaturvedi
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Correspondence to Bin-Bing S Zhou.

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Chaturvedi, P., Eng, W., Zhu, Y. et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18, 4047–4054 (1999). https://doi.org/10.1038/sj.onc.1202925

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