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Gene Review

TLK1  -  tousled-like kinase 1

Homo sapiens

Synonyms: KIAA0137, PKU-BETA, PKU-beta, Serine/threonine-protein kinase tousled-like 1, Tousled-like kinase 1
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Disease relevance of TLK1


High impact information on TLK1

  • Chk1 phosphorylates Tlk1 on serine 695 (S695) in vitro, and this UCN-01- and caffeine-sensitive site is phosphorylated in vivo in response to DNA damage [2].
  • Substitution of S695 to alanine impaired efficient downregulation of Tlk1 after DNA damage [2].
  • In human cells, two structurally similar Tlks, Tlk1 and Tlk2, were recently shown to be cell cycle-regulated kinases with maximal activities during S phase [3].
  • 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 [4].
  • We also demonstrate that TLK suppression is dependent on the presence of a functional Nijmegan Breakage Syndrome protein (NBS1) [4].

Biological context of TLK1

  • TLK activity is rapidly suppressed by DNA damage and by inhibitors of replication [4].
  • 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 [4].
  • The human Tousled-like kinases 1 and 2 (TLK) have been shown to be active during S phase of the cell cycle [4].
  • 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) [4].
  • The function of TLK1 is not well known, although knockout of the gene in Drosophila or expression of a dominant negative mutant in mouse cells causes loss of nuclear divisions and missegregation of chromosomes probably, due to alterations in chromatin remodeling capacity [5].

Anatomical context of TLK1


Associations of TLK1 with chemical compounds

  • The deduced aa sequences of PKU-alpha and PKU-beta contained typical serine/threonine PK domains at the C-terminal region and were 86% identical to each other, indicating that they belong to the same PK family [1].

Enzymatic interactions of TLK1

  • Furthermore, it could be shown that Tlk1 phosphorylates immunoprecipitated p68 [6].

Other interactions of TLK1

  • Identification of the human DEAD-box protein p68 as a substrate of Tlk1 [6].

Analytical, diagnostic and therapeutic context of TLK1


  1. cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal. Yamakawa, A., Kameoka, Y., Hashimoto, K., Yoshitake, Y., Nishikawa, K., Tanihara, K., Date, T. Gene (1997) [Pubmed]
  2. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. Groth, A., Lukas, J., Nigg, E.A., Silljé, H.H., Wernstedt, C., Bartek, J., Hansen, K. EMBO J. (2003) [Pubmed]
  3. Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Silljé, H.H., Nigg, E.A. Curr. Biol. (2001) [Pubmed]
  4. Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Krause, D.R., Jonnalagadda, J.C., Gatei, M.H., Sillje, H.H., Zhou, B.B., Nigg, E.A., Khanna, K. Oncogene (2003) [Pubmed]
  5. The radioresistance kinase TLK1B protects the cells by promoting repair of double strand breaks. Sunavala-Dossabhoy, G., Balakrishnan, S.K., Sen, S., Nuthalapaty, S., De Benedetti, A. BMC Mol. Biol. (2005) [Pubmed]
  6. Identification of the human DEAD-box protein p68 as a substrate of Tlk1. Kodym, R., Henöckl, C., Fürweger, C. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  7. Purification and identification of a protein kinase activity modulated by ionizing radiation. Kodym, R., Mayerhofer, T., Ortmann, E. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
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