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

The gene Tousled of Arabidopsis Thaliana encodes a protein kinase which, wh en 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 prot ein localizes almost exclusively mammalian cells rendered them more resista nt to ionizing radiation OR). Purified TLK1S phosphorylated histone H3 at S -10 with high specificity both in a mis of core histones and in isolated ch romatin, suggesting that histone H3 is a physiological substrate for TLK1B, Moreover, overexpression of TLK1B in transfected cells resulted in a highe r degree of H3 phosphorylation. Expression of TLK1B in a yeast strain that harbors a temperature-sensitive mutation of the major H3 kinase, IpI1, comp lemented the growth defect; restored normal levels of histone H3 phosphoryl ation; and increased their resistance to IR. Phosphorylation of H3 has been linked to the activation of the immediate-early gems upon mitogenic stimul ation, and to chromatin condensation during mitotic/meiotic events, A possi ble role for TLK1B in radioprotection is discussed.