DDX3X

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.

DDX3X has been shown to play an important role in translation initiation by interacting with the ribosome complex and unwinding and resolving 5´ UTR, particularly those with a complex structure, ahead of ribosome scanning. This interaction with the translational machinery is mediated by amino-acids at position 38–44. A reporter for the function and activity of DDX3X in 5´ UTR processing, named helicase activity reporter for translation (HART), was used to uncover the structures that are unwound by DDX3X.

DDX3X attenuates RNA-RNA interactions within G3BP1-driven RNP granules. Destabilization of these granules frees mRNA transcripts that were sequestered in the granules, restoring their availability and translatability.

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.

References

References

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2. (Oct 1998). "Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23". Cytogenetics and Cell Genetics.
3. "Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked".
4. Wilkins, Kevin C.. (2024-08-01). "A novel reporter for helicase activity in translation uncovers DDX3X interactions". RNA.
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6. (December 2024). "G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability". Molecular Cell.
7. (October 2004). "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function". Cell.
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