DHX9, also known as RNA Helicase A (RHA) or Nuclear DNA Helicase II (NDH II), is a protein found within human cells. It belongs to the DExH-box family of RNA helicases, a group of enzymes involved in altering RNA structure. These proteins are broadly involved in processes that alter the structure of RNA, playing roles in cellular function. DHX9 is a multi-domain protein, with distinct regions contributing to its diverse activities.
The Core Function of DHX9
DHX9 acts as an ATP-dependent nucleic acid helicase, an enzyme that unwinds double-stranded DNA and RNA, as well as DNA-RNA complexes. This unwinding activity is driven by the hydrolysis of ATP, which separates nucleic acid strands. This enzymatic action proceeds with a specific directionality, unwinding in a 3′ to 5′ direction relative to the displaced strand.
The unwinding of nucleic acids by DHX9 is a foundational process, making genetic material accessible for other cellular machinery. For instance, DNA must be unwound to be replicated or transcribed, and RNA structures often need to be remodeled for processing or translation. DHX9 shows a preference for unwinding more complex, multi-stranded nucleic acid structures, such as triplex DNA. This structural preference suggests its specialized roles in basic cellular processes.
DHX9’s Diverse Roles in Cellular Health
DHX9’s core helicase function enables its participation in a wide array of normal cellular processes, including those related to gene expression. It is involved in transcription, the process where DNA is converted into RNA, and in RNA splicing, which removes non-coding regions from RNA molecules. DHX9 also contributes to translation, where RNA is used as a template to synthesize proteins, and plays a part in the nuclear export of certain RNA molecules.
Beyond gene expression, DHX9 maintains genomic stability, ensuring the cell’s DNA remains intact. It contributes to accurate DNA replication and is involved in DNA repair mechanisms. DHX9 helps resolve harmful secondary double-stranded RNA structures, preventing them from triggering cellular stress responses. This broad involvement highlights its importance in cellular health.
DHX9 and Disease
Dysregulation or abnormal function of DHX9 is linked to various disease states, particularly in cancer and viral infections. In cancer, DHX9 can promote tumor growth, metastasis, and drug resistance. For example, its elevated expression is observed in multiple cancer types, including colorectal cancer, and its activity can influence the expression of genes associated with cancer progression. DHX9’s involvement in the p53 pathway, a tumor suppressor, also connects it to cancer progression, with DHX9 inhibition sometimes leading to p53-mediated cell death.
DHX9’s activity can contribute to multidrug resistance in cancer cells, such as in leukemia and colorectal cancer, by influencing the expression of resistance-associated genes. DHX9 also plays a role in viral infections, where viruses may either exploit its functions for their replication or be inhibited by its antiviral activities. For instance, DHX9 has both proviral and antiviral roles against various RNA and DNA viruses, and it can form “antiviral granules” that restrict viral replication. Depleting DHX9 can also induce the formation of double-stranded RNA, triggering an antitumor immune response in certain cancers like small cell lung cancer.
DHX9 as a Research Focus and Therapeutic Target
Given its multifaceted roles in cellular processes and disease, DHX9 has become a significant focus in scientific research, particularly for its potential as a therapeutic target. Researchers are actively studying DHX9 due to its involvement in various cancers, including breast, ovarian, colorectal, endometrial, and gastric cancers. Inhibiting DHX9 exploits specific vulnerabilities in these tumor types, leading to cancer-specific cell death.
Ongoing research includes the development of small molecule inhibitors that target DHX9’s enzymatic activity. For example, ATX968 is an orally available robust inhibitor that has shown promise in preclinical studies, leading to tumor growth inhibition. These efforts aim to develop new drugs that can either directly impair tumor growth or enhance the effectiveness of existing therapies. While challenges exist in targeting such a broadly functional protein, the early results suggest a promising avenue for future therapeutic interventions.