Abstract
Checkpoint kinase 1 (Chk1) mediates diverse cellular responses to genotoxic stress, regulating the network of genome-surveillance pathways that coordinate cell cycle progression with DNA repair. Chk1 is essential for mammalian development and viability, and has been shown to be important for both S and G2 checkpoints. We now present evidence that the HTLV-1 Tax protein interacts directly with Chk1 and impairs its kinase activities in vitro and in vivo. The direct and physical interaction of Chk1 and Tax was observed in HTLV-1-infected T cells (C81, HuT 102 and MT-2) and transfected fibroblasts (293 T) by coimmunoprecipitation and by in vitro GST pull-down assays. Interestingly, Tax inhibited the kinase activity of Chk1 protein in in vitro and in vivo kinase assays. Consistent with these results, Tax inhibited the phosphorylation-dependent degradation of Cdc25A and G2 arrest in response to γ-irradiation (IR) in a dose-dependent manner in vivo. The G2 arrest did not require Chk2 or p53. These studies provide the first example of a viral transforming protein targeting Chk1 and provide important insights into checkpoint pathway regulation.
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Acknowledgements
We thank Dr Cynthia Pise-Masison and members of Dr Brady's laboratory for helpful discussion, and the FACS core facility of CCR, NCI, NIH for flow cytometry analysis. We also thank Drs Bert Vogelstein and Fred Bunz for providing HCT116p21+/+, p53−/−, and Chk2−/− cell lines.
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Supplementary Information accompanies the paper on Oncogene website: (http://www.nature.com/onc).
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Figure S1
Western blot of immunoprecipitates from HTLV-1-transformed C81cell lysates using a polyclonal anti-Chk1 antibody or control IgG antibody for 2-h or overnight incubation. The upper panel shows the coprecipitated Tax level. The lower panel indicates the amount of Chk1 precipitated. IP, immunoprecipitation; o/n, overnight (JPG 87 kb)
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Park, H., Jeong, JH., Chung, J. et al. Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1. Oncogene 23, 4966–4974 (2004). https://doi.org/10.1038/sj.onc.1207644
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DOI: https://doi.org/10.1038/sj.onc.1207644
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