HGNC Approved Gene Symbol: DCK
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:70,993,649-71,030,914 (from NCBI)
Deoxycytidine kinase (DCK; EC 2.7.1.74) is responsible for the phosphorylation of several deoxyribonucleosides and their analogs. It has broad substrate specificity for deoxyadenosine (dAdo) and deoxyguanosine (dGuo) as well as for deoxycytidine (dCyd). It is also a key enzyme in the phosphorylation of a variety of antineoplastic and antiviral nucleoside analogs including cytosine arabinoside (araC) and dideoxycytidine (ddCyd); deficiency of deoxycytidine kinase activity mediates resistance to these drugs (summary by Chottiner et al., 1991).
Huang et al. (1989) cloned the DCK gene. Similarities to previously studied proteins such as the beta subunit of prolyl-4-hydroxylase (176790) were revealed. Chottiner et al. (1991) also cloned human deoxycytidine kinase from a T-lymphoblast DNA library. The cDNA sequence encoded a 30.5-kD protein corresponding to the subunit molecular mass of the purified protein. The authors of Huang et al. (1989) subsequently discovered that the sequence they had thought to represent DCK is in fact the human homolog of ERp72, the function of which is not yet known, and published a correction; the gene studied by Chottiner et al. (1991) is the true deoxycytidine kinase.
By isolating genomic clones of DCK, Song et al. (1993) demonstrated that the gene extends over more than 34 kb of DNA and that the coding region is composed of 7 exons ranging in size from 90 to 1,544 bp. The 5-prime flanking region is highly G+C rich and contains 4 regions that are potential Sp1 binding sites.
By PCR using genomic primers flanking the third exon of the DCK gene, Song et al. (1993) demonstrated in a human-hamster hybrid panel and in murine-human hybrid cell lines that the DCK gene is located on human chromosome 4. By fluorescence in situ hybridization, Stegmann et al. (1993) assigned the DCK gene to 4q13.3-q21.1.
Human deoxyribonucleoside kinases are required for the pharmacologic activity of several clinically important anticancer and antiviral nucleoside analogs. Human deoxycytidine kinase and thymidine kinase-1 (188300) had been described as cytosolic enzymes, whereas human deoxyguanosine kinase (601465) and thymidine kinase-2 (188250) were believed to be located in the mitochondria. Johansson et al. (1997) expressed 4 human deoxyribonucleoside kinases as fusion proteins with the green fluorescent protein to study their intracellular locations in vivo. They found that the human deoxycytidine kinase is located in the cell nucleus, and the human deoxyguanosine kinase in mitochondria. The fusion proteins between green fluorescent protein and thymidine kinases 1 and 2 were both predominantly located in the cytosol. Site-directed mutagenesis of a putative nuclear targeting signal, identified in the primary structure of deoxycytidine kinase, completely abolished nuclear import of the protein. Reconstitution of a deoxycytidine kinase-deficient cell line with the wildtype nuclear or the mutant cytosolic enzymes restored sensitivity toward anticancer nucleoside analogs.
Chottiner, E. G., Shewach, D. S., Datta, N. S., Ashcraft, E., Gribbin, D., Ginsburg, D., Fox, I. H., Mitchell, B. S. Cloning and expression of human deoxycytidine kinase cDNA. Proc. Nat. Acad. Sci. 88: 1531-1535, 1991. [PubMed: 1996353] [Full Text: https://doi.org/10.1073/pnas.88.4.1531]
Huang, S.-H., Tomich, J. M., Wu, H., Jong, A., Holcenberg, J. Human deoxycytidine kinase: sequence of cDNA clones and analysis of expression in cell lines with and without enzyme activity. J. Biol. Chem. 264: 14762-14768, 1989. Note: Erratum: J. Biol. Chem. 266: 5353 only, 1991. [PubMed: 2549034]
Johansson, M., Brismar, S., Karlsson, A. Human deoxycytidine kinase is located in the cell nucleus. Proc. Nat. Acad. Sci. 94: 11941-11945, 1997. [PubMed: 9342341] [Full Text: https://doi.org/10.1073/pnas.94.22.11941]
Song, J. J., Walker, S., Chen, E., Johnson, E. E., II, Spychala, J., Gribbin, T., Mitchell, B. S. Genomic structure and chromosomal localization of the human deoxycytidine kinase gene. Proc. Nat. Acad. Sci. 90: 431-434, 1993. [PubMed: 8421671] [Full Text: https://doi.org/10.1073/pnas.90.2.431]
Stegmann, A. P. A., Honders, M. W., Bolk, M. W. J., Wessels, J., Willemze, R., Landegent, J. E. Assignment of the human deoxycytidine kinase (DCK) gene to chromosome 4 band q13.3-q21.1. Genomics 17: 528-529, 1993. [PubMed: 8406512] [Full Text: https://doi.org/10.1006/geno.1993.1365]