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A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed

Oncogene volume 20, pages 726–738 (2001)Cite this article

Abstract

The gene Tousled of Arabidopsis Thaliana encodes a protein kinase which, when mutated, results in abnormal flower development. From a library of mRNAs that are translationally upregulated by overexpression of the translation initiation factor 4E, we identified a mammalian Tousled Like kinase (TLK1B). The human TLK1B mRNA contains a 5′UTR 1088-nt-long with two upstream AUG codons, and was found to be very inhibitory for translation. The TLK1B protein localizes almost exclusively to the nuclei. TLK1B overexpression in mammalian cells rendered them more resistant to ionizing radiation (IR). Purified TLK1B phosphorylated histone H3 at S10 with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone H3 is a physiological substrate for TLK1B. Moreover, overexpression of TLK1B in transfected cells resulted in a higher degree of H3 phosphorylation. Expression of TLK1B in a yeast strain that harbors a temperature-sensitive mutation of the major H3 kinase, Ipl1, complemented the growth defect; restored normal levels of histone H3 phosphorylation; and increased their resistance to IR. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. A possible role for TLK1B in radioprotection is discussed.

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Acknowledgements

We are indebted to Dr T Nagase (Kazusa, DNA research Institute, Chiba, Japan) for the TLK1B clone (KIAA0137). We thank Dr T Date (Kanazawa Medical School, Japan) for the gift of PKUβ antiserum; and Dr S Grimes for the preparation of histones. We thank Dr Kelly Tatchell (in our department) for giving us the ipl1-2 strain, and for communicating results about its activity on histone H3 ahead of publication. We thank A Magherini for technical help with the kinase assays, and Dr D Gross for comments and suggestions about this work. This work was supported by grant CA69148 from the National Institutes of Health. C Anthony is recipient of a fellowship from the Feist-Weiller Cancer Center.

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  1. Yuan Li and Robert DeFatta: Y Li and R DeFatta contributed equally to the paper

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, and the Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, Louisiana, USA

    Yuan Li, Robert DeFatta, Charles Anthony, Gulshan Sunavala & Arrigo De Benedetti

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  1. Yuan Li
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Li, Y., DeFatta, R., Anthony, C. et al. A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed. Oncogene 20, 726–738 (2001). https://doi.org/10.1038/sj.onc.1204147

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