DDX1: A Versatile RNA Helicase

DDX1 (Dead-Box Helicase 1) belongs to the DEAD-Box family of ATP-dependent RNA helicases, whose members are collectively involved in almost all aspects of RNA processing: from transcription to remodeling to degradation. They are named for the central Asp-Glu-Ala-Asp (DEAD) sequence they all possess. The 35 human DEAD-Box proteins comprise the largest family of helicases known.

DDX1 was first found due to its overexpression in retinoblastoma. It is a 740 amino acid protein, weighing in at about 82 kDa. From bow to stern, it consists of an N-terminal Rec A-like domain containing a Q motif that mediates ATP binding and hydrolysis, a SPRY motif involved in protein-protein recognition, and the signature DEAD sequence. This is followed by a hinge region and a C-terminal Rec A domain. While both domains share and cooperate in conformationally dictated ATP binding and hydrolysis, RNA binding, and helicase functions, the N-terminal domain principally orchestrates ATP binding and hydrolysis, while the C-terminal domain controls RNA binding and helicase activities. The Q motif is unique to DEAD-Box helicases, but DDX1 is the only DEAD-Box helicase to possess a SPRY motif.¹

DDX1 Juggles Many Roles

In its RNA helicase capacity, DDX1 regulates translation initiation, nuclear RNA splicing, ribosome synthesis, and mRNA synthesis/stability. However, as research progresses, more roles for DDX1 are constantly emerging. While it is usually found in the nucleus, DDX1 is also found in the cytoplasm of transformed cells. It binds to poly(A) RNA and may influence the polyadenylation and 3′-end cleavage of mRNA. Even though DDX1’s ATPase acts solely on RNA and not DNA, it does help to clear RNA from DNA double-strand breaks and aid in repair. DDX1 is also a component of the t-RNA-splicing ligase complex. Most recently, DDX1 has been found to participate in the Drosha microprocessor that directs the transcriptional maturation of certain miRNAs.²

Involvement in Innate Immunity

In the area of innate immunity, DDX1 participates in the TICAM1 complex, a cytoplasmic sensor of viral double-stranded (ds) RNA. DDX1 recognizes and binds both short and long stretches of dsRNA. When activated, this complex activates cellular antiviral responses and the release of inflammatory cytokines. Similarly, DDX1 acts with RELA to enhance NF-kappa-Beta expression. DDX1 interacts with Viral Protein 3D in Foot and Mouth Disease Virus to inhibit its replication and induce the Type I IFN response. DDX1 also binds the NSP14 protein of Transmissible Gastroenteritis Virus to induce Interferon-Beta. However, the NSP14s from Coronavirus Infectious Bronchitis Virus and SARS-CoV have evolved to interact with DDX1 in a way that blunts its innate immunity function and enhances viral replication.³

Targeting DDX1 for Disease

From the time it was identified, DDX1’s role in cancer has only expanded. While this helicase is present in all cells and is most abundant in testicular tissue, its abnormal abundance in transformed tissues is proving to be important in cancer progression. DDX1’s influence on transcription, RNA structures, and metastasis is emerging in testicular, colorectal, liver, ovarian, and breast cancer.⁴

Recent work on the influence of hyperlipidemia on insulin resistance has revealed that high levels of palmitate ingestion repress the production of insulin by interfering with proper DDX1 processing of insulin mRNA. As a result, adequate insulin isn’t produced, and blood glucose levels dysregulate.⁵

The true extent of DDX1’s influence can only be revealed through further investigation.

References

1. Zhang, L. and Li, X. (2021) DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy. Cells, 10(6), 1540. Review. https://doi.org/10.3390/cells10061540
2. Cargill, M. et al. (2021) DEAD-Box RNA Helicases and Genome Stability. Genes, 12(10), 1471. Review. https://doi.org/10.3390/genes12101471
3. Ali, M.A.M. (2021) DEAD-box RNA helicases: The driving forces behind RNA metabolism at the crossroad of viral replication and antiviral innate immunity. Virus Research, 296, 198352. Review. https://doi.org/10.1016/j.virusres.2021.198352
4. Tabassum, S. and Ghosh, M.K. (2022) DEAD-box RNA helicases with special reference to p68: Unwinding their biology, versatility, and therapeutic opportunity in cancer. Genes & Diseases, in Press. Review. https://doi.org/10.1016/j.gendis.2022.02.008
5. Li, Z. et al. (2018) RNA-binding protein DDX1 is responsible for fatty acid-mediated repression of insulin translation. Nucleic Acids Research, 46(22), 12052-12066. https://doi.org/10.1093/nar/gky867