Alternative titles; symbols
HGNC Approved Gene Symbol: DDX1
Cytogenetic location: 2p24.3 Genomic coordinates (GRCh38): 2:15,591,868-15,631,101 (from NCBI)
DEAD box proteins, such as DDX1, are putative RNA helicases that have a characteristic asp-glu-ala-asp (DEAD) box motif. By altering RNA secondary structure, DEAD box proteins can influence translation initiation, splicing, and ribosome and spliceosome assembly (summary by Godbout and Squire, 1993).
Godbout and Squire (1993) obtained a clone for a DEAD box gene by differential screening of a cDNA library made by selecting nonhybridizing cDNAs from 2 retinoblastoma cell lines after subtraction with poly(A)+ RNA from a colon cancer cell line and fetal tissue. The 2.4-kb cDNA, designated HuDBP-RB (Human DEAD box protein-Retinoblastoma) by the authors, encodes a 739-amino acid protein. Northern blot analysis showed highest expression in 2 retinoblastoma cell lines and in tissues of neuroectodermal origin, including retina, brain, and spinal cord. Southern blot analysis showed that the DDX1 gene was coamplified with the MYCN protooncogene (164840) in high-expressing retinoblastoma lines.
By Northern blot analysis of several mouse tissues, Tanaka et al. (2009) detected highest Ddx1 expression in testis. In developing mouse embryo, Ddx1 was expressed from the sexually indifferent gonad at 11.5 days postcoitus (dpc) to fetal testis at 19.5 dpc. Ddx1 expression was maintained in adult testis. Immunohistochemical analysis of mouse testis and in situ hybridization of human testis revealed DDX1 expression in a subset of cells near the basement membrane of the seminiferous tubule. In mouse, Ddx1 expression gradually decreased during spermatogenesis. DDX1 was also expressed in human seminoma and embryonal carcinoma tumors.
Using mouse cDNA microarrays and RT-PCR, Tanaka et al. (2009) showed that small interfering RNA-mediated knockdown of Ddx1 in a mouse spermatogonia-derived cell line reduced expression of the cyclin D2 (CCND2; 123833), Gdf3 (606522), and Cd9 (143030) genes. These 3 genes are located in the stem cell gene cluster on mouse chromosome 6 and human chromosome 12p13.3. Reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays confirmed binding and activation of the cyclin D2 gene by mouse Ddx1. Knockdown of DDX1 in the NEC8 human embryonal carcinoma-derived cell line reduced expression of cyclin D2 and CD9, but not GDF3. Knockdown of DDX1 in NEC8 cells also reduced the ability of NEC8 cells to induce tumors when transplanted into athymic nude mice. Tanaka et al. (2009) concluded that DDX1 is a stem cell regulator that contributes to testicular germ cell tumors when overexpressed.
By immunoprecipitation and protein pull-down analyses using biotinylated poly I:C, Zhang et al. (2011) identified a cytosolic, endosome-independent sensor of viral nucleotides consisting of the RNA helicases Ddx1, Ddx21 (606357), and Dhx36 (612767) and the adaptor molecule Trif (TICAM1; 607601) in mouse myeloid dendritic cells (mDCs). The double-stranded RNA (dsRNA) sensors Pkr (EIF2AK2; 176871) and Lgp2 (DHX58; 608588) were also precipitated. Knockdown of each helicase via short hairpin RNA blocked the ability of mDCs to mount type I interferon (see 147660) and cytokine responses to poly I:C, influenza A, and reovirus. Ddx1 bound poly I:C through its helicase A domain, while Dhx36 and Ddx21 bound the TIR domain of Trif via their HA2-DUF and PRK domains, respectively. Zhang et al. (2011) concluded that the DDX1-DDX21-DHX36 complex is a dsRNA sensor that uses the TRIF pathway to activate type I interferon responses in the cytosol of mDCs.
Popow et al. (2014) found that archease (ZBTB8OS; 615891), in cooperation with DDX1, stimulated pre-tRNA splicing by RTCB (613901). Cross-linking of HEK293 cell proteins revealed a protein complex that included epitope-tagged archease, RTCB, FAM98B (616142), and DDX1. Archease required GTP to stimulate RTCB activity, and ATP hydrolysis by DDX1 was required for maximal RTCB stimulation. Popow et al. (2014) concluded that archease facilitates DDX1-dependent formation of RTCB-guanylate intermediates that are required for pre-tRNA ligation.
By mass spectrometric analysis of tryptic peptides that immunoprecipitated with CLE (C14ORF166; 610858) from HEK293T cells, Perez-Gonzalez et al. (2014) identified a protein complex of 220 to 480 kD that included DDX1, HSPC117 (RTCB), and FAM98B, in addition to CLE; the complex also included RNA. Short hairpin RNA-dependent downregulation of CLE in HEK293T cells reduced nuclear and cytosolic accumulation of DDX1, HSPC117, and FAM98B. Overexpression of CLE stabilized the complex in both compartments, and RNase treatment caused partial dissociation of CLE and HSPC117, suggesting that it is a ribonucleoprotein complex. Inhibition of transcription reduced nuclear import of the complex, resulting in cytosolic accumulation of DDX1.
Godbout and Squire (1993) mapped the DDX1 gene to chromosome 2p24 by fluorescence in situ hybridization.
A gene reported by Kitajima et al. (1994), which was designated DDX7 by the HUGO Nomenclature Committee, was later determined to be bacterial rather than human sequence.
Godbout, R., Squire, J. Amplification of a DEAD box protein gene in retinoblastoma cell lines. Proc. Nat. Acad. Sci. 90: 7578-7582, 1993. [PubMed: 7689221] [Full Text: https://doi.org/10.1073/pnas.90.16.7578]
Kitajima, Y., Yatsuki, H., Zhang, R., Matsuhashi, S., Hori, K. A novel human homologue of a DEAD-box RNA helicase family. Biochem. Biophys. Res. Commun. 199: 748-754, 1994. [PubMed: 8135819] [Full Text: https://doi.org/10.1006/bbrc.1994.1292]
Perez-Gonzalez, A., Pazo, A., Navajas, R., Ciordia, S., Rodriguez-Frandsen, A., Nieto, A. hCLE/C14orf166 associates with DDX1-HSPC117-FAM98B in a novel transcription-dependent shuttling RNA-transporting complex. PLoS One 9: e90957, 2014. Note: Electronic Article. [PubMed: 24608264] [Full Text: https://doi.org/10.1371/journal.pone.0090957]
Popow, J., Jurkin, J., Schleiffer, A., Martinez, J. Analysis of orthologous groups reveals archease and DDX1 as tRNA splicing factors. Nature 511: 104-107, 2014. [PubMed: 24870230] [Full Text: https://doi.org/10.1038/nature13284]
Tanaka, K., Okamoto, S., Ishikawa, Y., Tamura, H., Hara, T. DDX1 is required for testicular tumorigenesis, partially through the transcriptional activation of 12p stem cell genes. Oncogene 28: 2142-2151, 2009. [PubMed: 19398953] [Full Text: https://doi.org/10.1038/onc.2009.89]
Zhang, Z., Kim, T., Bao, M., Facchinetti, V., Jung, S. Y., Ghaffari, A. A., Qin, J., Cheng, G., Liu, Y.-J. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34: 866-878, 2011. [PubMed: 21703541] [Full Text: https://doi.org/10.1016/j.immuni.2011.03.027]