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The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1

Oncogene volume 28, pages 1366–1378 (2009)Cite this article

Abstract

Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68. However, it remains to be determined whether and how TTK/hMps1 responds to DNA damage. In this report, we present evidence that TTK/hMps1 can be induced by DNA damage in normal human fibroblasts. Interestingly, the induction depends on CHK2 because CHK2-targeting small interfering RNA or a CHK2 inhibitor abolishes the increase. Such induction is mediated through phosphorylation of TTK/hMps1 at Thr288 by CHK2 and requires the CHK2 SQ/TQ cluster domain/forkhead-associated domain. In cells, TTK/hMps1 phosphorylation at Thr288 is induced by DNA damage and forms nuclear foci, which colocalize partially with γ-H2AX. Reexpression of TTK/hMps1 T288A mutant in TTK/hMps1-knockdown cells causes a defect in G2/M arrest, suggesting that phosphorylation at this site participates in the proper checkpoint execution. Our study uncovered a regulatory loop between TTK/hMps1 and CHK2 whereby DNA damage-activated CHK2 may facilitate the stabilization of TTK/hMps1, therefore maintaining the checkpoint control.

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Acknowledgements

We thank the LC/MS/MS core of the Institute of Biomedical Sciences for the expert assistance in mass spectrometry. This work was supported by grants from Academia Sinica and National Science Council of Taiwan to S-Y Shieh.

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  1. Y-H Yeh

    Present address: 3Current address: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, 1 Section 1, Jen-Ai Road, Taipei 100, Taiwan.,

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Y-H Yeh, Y-F Huang, T-Y Lin & S-Y Shieh

  2. Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan

    Y-F Huang

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Correspondence to S-Y Shieh.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yeh, YH., Huang, YF., Lin, TY. et al. The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1. Oncogene 28, 1366–1378 (2009). https://doi.org/10.1038/onc.2008.477

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