DDX39B, or DEAD-box helicase 39B, is a human gene that provides instructions for making a specific protein. This protein belongs to the DEAD-box helicase family, characterized by a conserved Asp-Glu-Ala-Asp (DEAD) motif. DDX39B is also known as UAP56 or BAT1. It plays a role in intricate cellular processes, essential for proper cell function.
The Role of DDX39B in Cellular Processes
DDX39B functions as an RNA helicase, an enzyme that unwinds the double-stranded structure of RNA molecules, similar to a zipper. This unwinding is powered by ATP hydrolysis. This activity allows DDX39B to participate in many steps of RNA metabolism within the cell.
A primary role of DDX39B is in messenger RNA (mRNA) splicing. This process removes non-coding regions (introns) from a newly made RNA molecule and joins the coding regions (exons). DDX39B acts as a splicing factor, facilitating the association of U2 small nuclear ribonucleoprotein with pre-mRNA. This precise trimming and rejoining of RNA is similar to editing a film, where unnecessary scenes are cut to create a coherent story, ensuring the correct genetic information is conveyed.
Beyond splicing, DDX39B also influences gene expression regulation and the export of mRNA from the cell’s nucleus to its cytoplasm. mRNA acts as blueprints for building proteins; DDX39B helps ensure these blueprints are correctly prepared and delivered from the nucleus to the cytoplasm, where proteins are assembled. This precise transport is necessary for the cell to produce the right proteins at the right time and in the right amounts.
DDX39B also participates in ribosome biogenesis, the process of creating ribosomes, which are the cellular machinery for protein synthesis. It helps regulate pre-ribosomal RNA levels. These functions highlight DDX39B’s role in RNA production and management, essential for proper cell operation and overall health.
DDX39B and Human Health
When DDX39B does not function correctly, due to genetic mutations or altered expression, it can have significant consequences for human health. Dysfunction in this gene has been linked to various diseases, including certain cancers and neurodevelopmental disorders. The mechanisms often involve faulty protein production or impaired cellular processes.
In cancer, elevated DDX39B levels have been observed in several cancer types, promoting cell proliferation and colony formation. For instance, DDX39B facilitates the malignant progression of hepatocellular carcinoma (HCC), a type of liver cancer, by activating de novo lipid synthesis through its interaction with the SREBP1 protein. This suggests DDX39B can influence tumor growth by altering how cancer cells produce and use fats.
DDX39B has also been implicated in colorectal cancer progression. It enhances proliferation and metastasis by stabilizing DCLK1-B mRNA, a variant linked to cancer stemness. Additionally, it promotes aerobic glycolysis, also known as the Warburg effect, in colorectal cancer cells by enhancing the nuclear function of PKM2, a protein involved in metabolism. This metabolic reprogramming helps cancer cells grow and spread more aggressively.
Beyond cancer, DDX39B has been connected to neurodevelopmental disorders. For example, mutations in the related gene DDX3X, also an RNA helicase, are linked to intellectual disability and autism spectrum disorder. As both belong to the DEAD-box helicase family, disruptions in these RNA processing pathways can impact brain development.
A genetic variant in the 5′ untranslated region (UTR) of DDX39B can reduce its translation, increasing the risk of multiple sclerosis (MS). This variant shows a strong genetic and functional interaction with specific variants in IL7R exon 6, providing insight into the regulation of IL7R exon 6 splicing and its impact on MS risk. DDX39B also controls the expression of Forkhead Box P3 (FOXP3), a master transcriptional factor for T regulatory cells, influencing immune tolerance.
Investigating DDX39B
Scientists employ various research methods to study DDX39B’s roles in health and disease. Genetic studies identify specific mutations or variations in the DDX39B gene associated with particular health conditions. These investigations often involve sequencing the DNA of individuals with and without a disease to pinpoint genetic differences.
Molecular biology techniques are used to understand the function of the DDX39B protein at a detailed level. Researchers might use methods to observe how DDX39B interacts with RNA molecules, other proteins, and how its helicase activity is regulated. For example, cryo-electron microscopy has been used to reveal the structural mechanism of DDX39B regulation by complexes like human TREX-2, providing insights into its role in messenger ribonucleoprotein (mRNP) remodeling and nuclear mRNA export.
Cell culture and animal models are also valuable tools for studying DDX39B’s role in disease. Scientists can manipulate DDX39B levels or introduce mutations in cells grown in a lab or in model organisms like mice to observe the resulting effects on cellular processes and disease progression. For instance, studies have shown that DDX39B overexpression can enhance the proliferative and metastatic potential of colon adenocarcinoma cells both in vitro and in vivo.
Understanding DDX39B’s function and dysfunction holds promise for medical advancements. Its altered expression in various cancers suggests its potential as a biomarker for disease diagnosis or prognosis. For example, DDX39B is upregulated in hepatocellular carcinoma tissues and its levels predict a worse prognosis, making it a potential predictor of recurrence. DDX39B also presents itself as a potential target for new therapeutic interventions, such as drugs designed to modulate its activity. By targeting DDX39B, it may be possible to disrupt disease mechanisms, offering new avenues for treatment in conditions like colorectal cancer by preventing the ubiquitination and degradation of PKM2, which is linked to aerobic glycolysis.