DDX21 is an enzyme, classified as a DEAD-box helicase, that performs tasks necessary for life within human cells. Its primary function involves interacting with ribonucleic acid (RNA). DDX21 acts like a molecular zipper, unwinding and remodeling the complex, folded structures of RNA molecules.
This protein predominantly resides in the nucleolus, a compartment within the cell’s nucleus that serves as the main hub for constructing molecular machines. Here, DDX21 carries out its tasks, which are closely linked to the cell’s ability to grow and maintain itself.
Role in Building Cellular Machinery
The primary responsibility of DDX21 is its participation in the creation of ribosomes. Ribosomes are cellular structures that function as factories for protein synthesis, translating genetic code into the proteins that carry out cellular activities. Without a constant supply of new ribosomes, a cell cannot produce the proteins it needs to grow, repair itself, or divide.
DDX21 is involved in the assembly of these protein factories. The core components of ribosomes are made from ribosomal RNA (rRNA). This rRNA is first produced as a long, unprocessed precursor molecule that must be cut, folded, and modified to become functional. DDX21 directly binds to these precursor rRNA molecules within the nucleolus.
Its helicase activity is part of this maturation process. DDX21 uses energy to unwind incorrect folds and resolve tangled structures in the rRNA, allowing it to adopt its correct three-dimensional shape. This ensures that the rRNA can properly assemble with ribosomal proteins to form a functional ribosome subunit. It facilitates the processing of precursor rRNAs, such as 47S and 32S, into the mature 18S and 28S rRNA components.
The protein also assists in the chemical modification of rRNA, a step that helps stabilize the final structure. It works alongside small nucleolar RNAs (snoRNAs) to guide these modifications to the correct locations on the rRNA chain. Through these actions, DDX21 ensures the construction of the cell’s protein-producing machinery, a process known as ribosome biogenesis.
Involvement in Cancer Progression
The role of DDX21 in ribosome production connects it to cancer progression. Cancer is characterized by uncontrolled cell growth and division, which places a high demand on the cell’s resources. To sustain this rapid proliferation, cancer cells must synthesize vast quantities of proteins, requiring a dramatic increase in the number of ribosomes.
To meet this demand, many cancer cells increase their levels of DDX21. This elevated presence puts the cell’s ribosome factory into overdrive, supplying the building blocks needed for growth. For this reason, DDX21 is considered a proto-oncogene, a gene that can contribute to a cell becoming cancerous when its expression is increased.
Studies have documented abnormally high levels of DDX21 in many human cancers, including:
- Breast cancer
- Colorectal cancer
- Gastric cancer
- Lung cancer
In many of these cases, higher DDX21 expression is correlated with more aggressive tumors and poorer patient outcomes.
The mechanisms by which DDX21 promotes cancer can be direct. In some forms of neuroblastoma, the oncogene N-Myc drives the overproduction of DDX21, creating a feedback loop that accelerates tumor growth. In colorectal cancer, DDX21 activates other proteins involved in the cell cycle, such as CDK1, pushing cells to divide. By enhancing protein synthesis machinery and cell division signals, DDX21 becomes a factor in tumor progression.
Function in the Innate Immune Response
DDX21 also performs a function in the body’s defense system. It acts as a component of the innate immune system, the body’s first line of defense against pathogens like viruses. In this context, DDX21 functions as an intracellular sensor, detecting the presence of foreign genetic material.
When a virus infects a cell, it releases its genetic material to replicate, often in the form of double-stranded RNA. As part of a protein complex with DDX1 and DHX36, DDX21 recognizes this viral RNA in the cell’s cytoplasm. This recognition triggers an immediate defensive response.
Upon binding to the viral RNA, the DDX21-containing complex initiates a signaling cascade. This alerts the cell to the infection and culminates in the production of signaling molecules called type I interferons. To perform this function, DDX21 must move from its location in the nucleolus into the cytoplasm where the viral RNA is present.
Interferons are sent from the infected cell to its neighbors, warning them of the viral threat and instructing them to activate their own antiviral defenses. This process helps to limit the spread of the infection. This role demonstrates the protein’s functional versatility.
Potential as a Therapeutic Target
The dependency of many cancer cells on high levels of DDX21 makes the protein an attractive target for new cancer therapies. Since tumor cells require an overactive ribosome factory to proliferate, disrupting that factory by targeting DDX21 offers a way to attack this vulnerability.
Research is focused on developing small-molecule drugs that can inhibit the activity of DDX21. Such an inhibitor would block the protein’s helicase function, halting rRNA processing and shutting down ribosome production. This would starve cancer cells of the new proteins they need for growth, leading to a slowdown in proliferation and potentially cell death.
Laboratory studies have shown the promise of this approach. When scientists reduced the amount of DDX21 in breast and gastric cancer cell lines, they observed a decrease in cell proliferation and tumor growth. This provides a proof of concept that targeting DDX21 can have an anti-tumor effect.
Because many aggressive tumors are reliant on heightened ribosome biogenesis, DDX21 represents a promising molecular target. Further research aims to translate these findings into clinically effective treatments that could disrupt the processes that fuel tumor progression.