Disease relevance of TLK1

• We have cloned cDNAs for novel serine/threonine protein kinases (PK), termed PKU-alpha and PKU-beta, by screening a bacteriophage expression library for kinase activity [1].

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

• Overexpression of TLK1B, a spliced variant of the TLK1 mRNA, in a model mouse cell line increases it's resistance to ionizing radiation (IR) or the radiomimetic drug doxorubicin, also likely due to changes in chromatin remodeling [5].
• In addition, PKU-beta transiently expressed in COS-1 cells was predominantly nuclear [1].

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

• Sequence analysis of PKU-alpha and PKU-beta genes revealed that their open reading frames (ORF) were 2151 and 2361 nucleotides (nt) encoding polypeptides of 717 and 787 amino acid (aa) residues, respectively [1].
• The genes for PKU-alpha and PKU-beta were mapped to chromosome 17q23 and 8p12-p22, respectively, by fluorescence in situ hybridization [1].
• Mass spectrometric analysis of the purified 90 kDa fraction showed that pK90 is identical to Tlk1, which was verified by immunoprecipitation [7].

References