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  • Original Paper
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Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1

Oncogene volume 22, pages 5927–5937 (2003)Cite this article

Abstract

The human Tousled-like kinases 1 and 2 (TLK) have been shown to be active during S phase of the cell cycle. TLK activity is rapidly suppressed by DNA damage and by inhibitors of replication. Here we report that the signal transduction pathway, which leads to transient suppression of TLK activity after the induction of double-strand breaks (DSBs) in the DNA, is dependent on the presence of a functional ataxia-telangiectasia-mutated kinase (ATM). Interestingly, we have discovered that rapid suppression of TLK activity after low doses of ultraviolet (UV) irradiation or aphidicolin-induced replication block is also ATM-dependent. The nature of the signal that triggers ATM-dependent downregulation of TLK activity after UVC and replication block remains unknown, but it is not due exclusively to DSBs in the DNA. We also demonstrate that TLK suppression is dependent on the presence of a functional Nijmegan Breakage Syndrome protein (NBS1). ATM-dependent phosphorylation of NBS1 is required for the suppression of TLK activity, indicating a role for NBS1 as an adaptor or scaffold in the ATM/TLK pathway. ATM does not phosphorylate TLK directly to regulate its activity, but Chk1 does phosphorylate TLK1 GST-fusion proteins in vitro. Using Chk1 siRNAs, we show that Chk1 is essential for the suppression of TLK activity after replication block, but that ATR, Chk2 and BRCA1 are dispensable for TLK suppression. Overall, we propose that ATM activation is not linked solely to DSBs and that ATM participates in initiating signaling pathways in response to replication block and UV-induced DNA damage.

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Acknowledgements

This work was funded by the Queensland Cancer Fund and the National Health and Medical Research Council of Australia. KKK is supported by the Sylvia and Charles Viertel foundation. We thank Reuven Agami at Netherlands Cancer Institute for providing the pSuper Vector, Jeff Jackson at Glaxo Smith Kline for providing SB218078, Yossi Shiloh for the L3 cell line, Patrick Concannon for the NBS1 and 343A mutant complemented cells and Karen Hobson for tissue culture assistance. We also thank Professor Kay Ellem, Dr Nuri Gueven and Dr Katie Sloper for useful discussions and critical reading of the manuscript.

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Authors and Affiliations

  1. Cancer and Cell Biology Division, Signal Transduction Lab, Queensland Institute of Medical Research, 300 Herston Rd, Qld 4029, Australia

    Darren R Krause, Jyoti C Jonnalagadda, Magtouf H Gatei & Kumkum Khanna

  2. Department of Cell Biology, Max-Planck Institute for Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, Germany

    Herman HW Sillje & Erich A Nigg

  3. Incyte Genomics Inc., 1090 Elkton Rd, S113, Newark, 19714, DE, USA

    Bin-Bing Zhou

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Correspondence to Darren R Krause.

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Krause, D., Jonnalagadda, J., Gatei, M. et al. Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene 22, 5927–5937 (2003). https://doi.org/10.1038/sj.onc.1206691

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