DDX3X

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.

DDX3X
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2I4I, 2JGN, 3JRV, 4O2C, 4O2E, 4O2F, 4PX9, 4PXA, 5E7J, 5E7M, 5E7I
Identifiers
Aliases	DDX3X, DBX, DDX14, DDX3, HLP2, CAP-Rf, MRX102, DEAD-box helicase 3, X-linked, DEAD-box helicase 3 X-linked, MRXSSB
External IDs	OMIM: 300160; MGI: 103064; HomoloGene: 3425; GeneCards: DDX3X; OMA:DDX3X - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xp11.4 Start 41,333,348 bp End 41,364,472 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A1.1|X 8.17 cM Start 13,147,209 bp End 13,160,291 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Epithelium of choroid plexus oocyte sperm secondary oocyte palpebral conjunctiva lactiferous duct tibia mucosa of paranasal sinus skin of hip epithelium of colon Top expressed in maxillary prominence cumulus cell human fetus tail of embryo mandibular prominence primitive streak lacrimal gland genital tubercle epithelium of stomach ureter More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding nucleotide binding nucleoside-triphosphatase activity CTPase activity helicase activity poly(A) binding ribosomal small subunit binding RNA stem-loop binding DNA helicase activity transcription factor binding ATPase activity protein binding GTPase activity eukaryotic initiation factor 4E binding RNA binding nucleic acid binding mRNA 5'-UTR binding translation initiation factor binding hydrolase activity ATP binding RNA strand annealing activity cadherin binding protein serine/threonine kinase activator activity Cellular component cytoplasm eukaryotic translation initiation factor 3 complex nuclear speck membrane mitochondrial outer membrane cytosolic small ribosomal subunit mitochondrion cytoplasmic stress granule extracellular exosome nucleus extracellular region cytosol secretory granule lumen ficolin-1-rich granule lumen nucleolus Biological process stress granule assembly apoptotic process negative regulation of translation negative regulation of cysteine-type endopeptidase activity involved in apoptotic process intracellular signal transduction regulation of transcription, DNA-templated ribosome biogenesis negative regulation of intrinsic apoptotic signaling pathway immune system process chromosome segregation negative regulation of protein-containing complex assembly response to virus negative regulation of apoptotic process Wnt signaling pathway positive regulation of translation protein localization to cytoplasmic stress granule transcription, DNA-templated cellular response to osmotic stress positive regulation of G1/S transition of mitotic cell cycle intrinsic apoptotic signaling pathway positive regulation of cysteine-type endopeptidase activity involved in apoptotic process positive regulation of cell growth positive regulation of gene expression mature ribosome assembly cellular response to arsenic-containing substance negative regulation of cell growth positive regulation of chemokine (C-C motif) ligand 5 production RNA secondary structure unwinding positive regulation of apoptotic process positive regulation of viral genome replication viral process innate immune response positive regulation of translational initiation regulation of translation extrinsic apoptotic signaling pathway via death domain receptors positive regulation of transcription by RNA polymerase II positive regulation of interferon-beta production DNA duplex unwinding neutrophil degranulation positive regulation of protein serine/threonine kinase activity positive regulation of canonical Wnt signaling pathway translational initiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1654 13205 Ensembl ENSG00000215301 ENSMUSG00000000787 UniProt O00571 Q62167 RefSeq (mRNA) NM_001193416 NM_001193417 NM_001356 NM_024005 NM_001363819 NM_010028 NM_008015 RefSeq (protein) NP_001180345 NP_001180346 NP_001347 NP_001350748 NP_034158 Location (UCSC) Chr X: 41.33 – 41.36 Mb Chr X: 13.15 – 13.16 Mb PubMed search
Wikidata
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Function

DEAD box proteins are putative RNA helicases characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD). They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which interacts specifically with the hepatitis C virus core protein, resulting in a change in intracellular location. This gene has a homolog located in the nonrecombining region of the Y chromosome. The protein sequence is 91% identical between this gene and the Y-linked homolog.

Sub-cellular trafficking

DDX3X performs its functions in the cell nucleus and cytoplasm, exiting the nucleus via the exportin-1/CRM1 nuclear export pathway. It was initially reported that the DDX3X helicase domain was necessary for this interaction. At the same time, the canonical features of the trafficking pathway, namely the presence of a nuclear export signal (NES) on DDX3X and Ran-GTP binding to exportin-1, were dispensable. DDX3X binding to, and trafficking by, exportin-1 has since been shown not to require the DDX3X helicase domain and be explicitly NES- and Ran-GTP-dependent.

Role in cancer

DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which HIF1A activates its expression during hypoxia. Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A response element, as verified with chromatin immunoprecipitation and luciferase reporter assay. Since the expression of DDX3X is affected by the activity of HIF1A, the co-localization of these proteins has also been demonstrated in MDA-MB-231 xenograft tumor samples.

In HeLa cells, DDX3X is reported to control cell cycle progression through Cyclin E1. More specifically, DDX3X was shown to directly bind to the 5´ UTR of Cyclin E1, thereby facilitating the protein's translation. Increased protein levels of Cyclin E1 were demonstrated to mediate the transition of S phase entry.

Melanoma survival, migration, and proliferation are affected by DDX3X activity. Melanoma cells with low DDX3X expression exhibit a high migratory capacity, low proliferation rate, and reduced vemurafenib sensitivity. At the same time, high DDX3X-expressing cells are drug-sensitive, more proliferative, and less migratory. The translational effects on the melanoma transcription factor MITF can explain these phenotypes. The 5' UTR of the MITF mRNA contains a complex RNA regulon (IRES) that is bound and activated by DDX3X. Activation of the IRES leads to translation of the MITF mRNA. Mice injected with melanoma cells with a deleted IRES display more aggressive tumor progression, including increased lung metastasis. Interestingly, the DDX3X in melanoma is affected by vemurafenib via an undiscovered mechanism. It is unknown how the presence of vemurafenib downregulates DDX3X. However, reduced levels of DDX3X during drug treatment explain the development of drug-resistant cells frequently detected with low MITF expression.

Clinical significance

Mutations of the DDX3X gene are associated with medulloblastoma. In melanoma, the low expression of the gene is linked to poor distant metastasis-free survival. In addition, the mRNA level of DDX3X is lower in matched post-relapse melanoma biopsies for patients receiving vemurafenib and in progressing tumors.

Mutations of the DDX3X gene also cause DDX3X syndrome, which affects predominantly females and presents with developmental delay or disability, autism, ADHD, and low muscle tone.

See also

• Eukaryotic translation
• DExD/H box proteins
• DHX29

Further reading

• Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Research. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
• Owsianka AM, Patel AH (May 1999). "Hepatitis C virus core protein interacts with a human DEAD box protein DDX3". Virology. 257 (2): 330–40. doi:10.1006/viro.1999.9659. PMID 10329544.
• Mamiya N, Worman HJ (May 1999). "Hepatitis C virus core protein binds to a DEAD box RNA helicase". The Journal of Biological Chemistry. 274 (22): 15751–6. doi:10.1074/jbc.274.22.15751. PMID 10336476.
• Yagüe J, Alvarez I, Rognan D, Ramos M, Vázquez J, de Castro JA (June 2000). "An N-acetylated natural ligand of human histocompatibility leukocyte antigen (HLA)-B39. Classical major histocompatibility complex class I proteins bind peptides with a blocked NH(2) terminus in vivo". The Journal of Experimental Medicine. 191 (12): 2083–92. doi:10.1084/jem.191.12.2083. PMC 2193201. PMID 10859333.
• Kim YS, Lee SG, Park SH, Song K (October 2001). "Gene structure of the human DDX3 and chromosome mapping of its related sequences". Molecules and Cells. 12 (2): 209–14. doi:10.1016/S1016-8478(23)17085-3. PMID 11710523.
• Li J, Hawkins IC, Harvey CD, Jennings JL, Link AJ, Patton JG (November 2003). "Regulation of alternative splicing by SRrp86 and its interacting proteins". Molecular and Cellular Biology. 23 (21): 7437–47. doi:10.1128/MCB.23.21.7437-7447.2003. PMC 207616. PMID 14559993.
• Shu H, Chen S, Bi Q, Mumby M, Brekken DL (March 2004). "Identification of phosphoproteins and their phosphorylation sites in the WEHI-231 B lymphoma cell line". Molecular & Cellular Proteomics. 3 (3): 279–86. doi:10.1074/mcp.D300003-MCP200. PMID 14729942.
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
• Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT (October 2004). "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function". Cell. 119 (3): 381–92. doi:10.1016/j.cell.2004.09.029. PMID 15507209.
• Dayton AI (October 2004). "Within you, without you: HIV-1 Rev and RNA export". Retrovirology. 1: 35. doi:10.1186/1742-4690-1-35. PMC 526764. PMID 15516266.
• Krishnan V, Zeichner SL (December 2004). "Alterations in the expression of DEAD-box and other RNA binding proteins during HIV-1 replication". Retrovirology. 1: 42. doi:10.1186/1742-4690-1-42. PMC 543576. PMID 15588285.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
• Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, et al. (August 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods. 2 (8): 591–8. doi:10.1038/nmeth776. PMID 16094384. S2CID 20475874.
• Gevaert K, Staes A, Van Damme J, De Groot S, Hugelier K, Demol H, et al. (September 2005). "Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC". Proteomics. 5 (14): 3589–99. doi:10.1002/pmic.200401217. PMID 16097034. S2CID 895879.
• Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, et al. (March 2006). "DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control". Oncogene. 25 (14): 1991–2003. doi:10.1038/sj.onc.1209239. PMID 16301996.