Alternative titles; symbols
HGNC Approved Gene Symbol: TLK1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:170,990,823-171,231,293 (from NCBI)
The Tousled-like kinases, first described in Arabidopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly (Sillje et al., 1999).
By sequencing size-fractionated clones obtained from a myeloid leukemia cell line cDNA library, Nagase et al. (1995) cloned TLK1, which they designated KIAA0137. The deduced protein contains a protein kinase ATP-binding motif. Northern blot analysis detected expression of TLK1 in all tissues and cell lines examined except lung. Highest expression was detected in testis. Using a TLK2 (608439) clone as probe, Yamakawa et al. (1997) cloned TLK1, which they called PKU-beta, by screening a placenta cDNA library. The deduced 787-amino acid protein has a 5-domain structure, with N-terminal nuclear localization signals followed by a nucleotide binding motif, and a single catalytic domain near the C terminus. TLK1 shares 86% sequence identity with TLK2 overall, and 94% identity in the catalytic region. Northern blot analysis detected a 4.2-kb transcript expressed primarily in fetal kidney and liver, and in placenta. Immunofluorescence analysis of transfected COS-1 cells localized TLK1 to the nucleus. By PCR amplification of sequences similar to Arabidopsis TSL, followed by screening several cDNA libraries, Sillje et al. (1999) cloned TLK1. The deduced 718-amino acid protein has a calculated molecular mass of 81.9 kD. By RNase protection analysis of RNA isolated from various adult mouse organs, they found that Tlk1 is ubiquitously expressed. Western blot analysis detected endogenous HeLa cell TLK1 and TLK2 that migrated together at an apparent molecular mass of about 85 kD. Both proteins were also localized to the nucleus and were excluded from nucleoli.
Using myelin basic protein (MBP; 159430), casein (see 115450), and histone H1 (see 142709) as model substrates, Sillje et al. (1999) confirmed kinase activity in TLK1. MBP was readily phosphorylated, and histone was poorly phosphorylated. TLK1 was also capable of autophosphorylation, and only the phosphorylated form was catalytically active. Activity was also dependent upon asp-559 within the catalytic domain. The authors further found that both TLK1 and TLK2 displayed maximal activity during S phase of the cell cycle. Whereas protein levels were virtually constant throughout the cell cycle, both TLKs appeared to be regulated by cell-cycle-dependent phosphorylation. Inhibition of DNA replication caused a rapid loss of TLK activity, indicating that TLK function is tightly linked to ongoing DNA replication. With use of several human cell lines, Groth et al. (2003) determined that both TLK1 and TLK2 were novel targets of the DNA damage checkpoint. Both TLKs were rapidly inactivated upon exposure to ionizing radiation (IR), and the inactivation was directly mediated by the S-phase DNA damage checkpoint. IR-induced TLK1 inactivation required ATM (607585) and CHK1 (603078) function, and CHK1 phosphorylated TLK1 in vitro and in vivo at a site required for the inhibition of TLK1 in response to DNA damage. Groth et al. (2003) concluded that TLK1 is a target of CHK1 in the intra-S-phase DNA damage checkpoint. Krause et al. (2003) found that NBS1 (602667) was also part of the signaling pathway leading to transient suppression of TLK activity after double-strand breaks in the DNA, replication blockade, or low doses of ultraviolet irradiation.
By PCR analysis of a human-rodent cell hybrid panel, Nagase et al. (1995) mapped the TLK1 gene to chromosome 2. By FISH, Yamakawa et al. (1997) mapped the TLK1 gene to chromosome 8p22-p12. Hartz (2004) mapped the TLK1 gene to chromosome 2q31.1 based on an alignment of TLK1 sequences (GenBank AB004885 and GenBank D50927) with the genomic sequence.
Groth, A., Lukas, J., Nigg, E. A., Sillje, H. H. W., Wernstedt, C., Bartek, J., Hansen, K. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J. 22: 1676-1687, 2003. [PubMed: 12660173] [Full Text: https://doi.org/10.1093/emboj/cdg151]
Hartz, P. Personal Communication. Baltimore, MD. 2/2/2004.
Krause, D. R., Jonnalagadda, J. C., Gatei, M. H., Sillje, H. H. W., Zhou, B.-B., Nigg, E. A., Khanna, K. Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS and Chk1. Oncogene 22: 5927-5937, 2003. [PubMed: 12955071] [Full Text: https://doi.org/10.1038/sj.onc.1206691]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]
Sillje, H. H. W., Takahashi, K., Tanaka, K., Van Houwe, G., Nigg, E. A. Mammalian homologues of the plant Tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication. EMBO J. 18: 5691-5702, 1999. [PubMed: 10523312] [Full Text: https://doi.org/10.1093/emboj/18.20.5691]
Yamakawa, A., Kameoka, Y., Hashimoto, K., Yoshitake, Y., Nishikawa, K., Tanihara, K., Date, T. cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal. Gene 202: 193-201, 1997. [PubMed: 9427565] [Full Text: https://doi.org/10.1016/s0378-1119(97)00495-2]