ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene. [5] [6] [7]
ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene. [5] [6] [7]
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. 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 hepatitis C virus core protein resulting 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. [7]
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, while 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. [8] 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. [9]
DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which its expression is activated by HIF1A during hypoxia. [10] Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A response element, [10] 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. [10]
In HeLa cells DDX3X is reported to control cell cycle progression through Cyclin E1. [11] More specifically, DDX3X was shown to directly bind to the 5´ UTR of Cyclin E1 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of S phase entry. [11]
Melanoma survival, migration and proliferation is affected by DDX3X activity. [12] Melanoma cells with low DDX3X expression exhibit a high migratory capacity, low proliferation rate and reduced vemurafenib sensitivity. While high DDX3X expressing cells are drug sensitive, more proliferative and less migratory. These phenotypes can be explained by the translational effects on the melanoma transcription factor MITF. [12] 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. [12] Interestingly, the DDX3X in melanoma is affected by vemurafenib via an undiscovered mechanism. It is unknown how DDX3X is downregulated by the presence of vemurafenib. However, reduced levels of DDX3X during drug treatment explains the development of drug resistant cells frequently detected with low MITF expression. [12] [13] [14]
Mutations of the DDX3X gene are associated with medulloblastoma. [15] [16] [17] In melanoma the low expression of the gene is linked to a poor distant metastasis free survival. [12] 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.
Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the MITF gene.
Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.
Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.
RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.
DEAD box proteins are involved in an assortment of metabolic processes that typically involve RNAs, but in some cases also other nucleic acids. They are highly conserved in nine motifs and can be found in most prokaryotes and eukaryotes, but not all. Many organisms, including humans, contain DEAD-box (SF2) helicases, which are involved in RNA metabolism.
ATP-dependent RNA helicase A is an enzyme that in humans is encoded by the DHX9 gene.
Probable ATP-dependent RNA helicase DDX5 also known as DEAD box protein 5 or RNA helicase p68 is an enzyme that in humans is encoded by the DDX5 gene.
Tyrosinase-related protein 1, also known as TYRP1, is an intermembrane enzyme which in humans is encoded by the TYRP1 gene.
Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.
Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.
Probable ATP-dependent RNA helicase DDX6 is an enzyme that in humans is encoded by the DDX6 gene.
ATP-dependent RNA helicase DDX1 is an enzyme that in humans is encoded by the DDX1 gene.
MDA5 is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor capable of detecting viruses. It is generally believed that MDA5 recognizes double stranded RNA (dsRNA) over 2000nts in length, however it has been shown that whilst MDA5 can detect and bind to cytoplasmic dsRNA, it is also activated by a high molecular weight RNA complex composed of ssRNA and dsRNA. For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. The signaling cascades in MDA5 is initiated via CARD domain. Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response.
ATP-dependent RNA helicase DDX3Y is an enzyme that in humans is encoded by the DDX3Y gene.
ATP-dependent RNA helicase DDX39 is an enzyme that in humans is encoded by the DDX39 gene.
Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.
Integrator complex subunit 6 is a protein that in humans is encoded by the INTS6 gene.
In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.
Protein ZGRF1 is a protein encoded in the human by the ZGRF1 gene also known as C4orf21, that has a weight of 236.6 kDa. The ZGRF1 gene product localizes to the cell nucleus and promotes DNA repair by stimulating homologous recombination. This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. ZGRF1 is orthologous to nearly all eukaryotes. Functional domains of this protein link it to a series of helicases, most notably the AAA_12 and AAA_11 domains.
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