ATP-dependent RNA helicase DDX3X is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

that in humans is encoded by the ''DDX3X''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Function

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA

helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separat ...

s. 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 A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs ( snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to sp ...

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.

Sub-cellular trafficking

DDX3X performs its functions in the cell

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

and

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

, 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 Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase ...

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 its expression is activated by HIF1A 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 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of

S phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...

entry. Melanoma survival, migration and proliferation is affected by DDX3X activity. 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''. The 5' UTR of the

MITF 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. MITF is a basic helix-loop-helix leucine zipper transcription factor ...

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 Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

. 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.

Clinical significance

Mutations of the ''DDX3X'' gene are associated with

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

. In melanoma the low expression of the gene is linked to a 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 DDX3X syndrome is a genetic disorder that affects predominantly females. Patients with DDX3X syndrome may develop developmental delay or intellectual disability, autism, ADHD, and low muscle tone. The syndrome develops due to mutations of the DDX3 ...

, which affects predominantly females and presents with

developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, ...

or disability,

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

, ADHD, and

low muscle tone Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

Function

Sub-cellular trafficking

Role in cancer

Clinical significance

See also

References

Further reading