Proteins are large molecules that are absolutely crucial to the health of every single cell in the human body. However, the processes that determine which, and how many, proteins are available to a cell are complicated. Alternative splicing is a complex but insufficiently understood process. It is crucial to the production of proteins necessary to cell health. Researchers now believe that cancer cells also use this process to their own advantage. Indeed, they are still scratching the surface of how some of these processes work. One such process is alternative splicing, which gives cells access to a diverse range of proteins that originate from the same genetic source code but also serves different purposes within the cell, thereby ensuring its health. It is estimated that around 95% of human genes are alternatively spliced. However, when alternative splicing malfunctions, it can contribute to cancer’s growth, spread, and ability to develop resistance to chemotherapy.
Under normal conditions, alternative splicing is tightly regulated, but changes in alternative splicing are increasingly linked to a variety of human diseases, and in particular to cancer. Many researchers believe that by regulating alternative splicing, they could find a way to improve cancer therapies. Yet they still do not fully understand how this complex process works. Now, researchers from the Institute of Cancer Research in London, United Kingdom, have made fresh discoveries about the structure and function of DHX8. This protein plays an important role in alternative splicing, and its activity could help explain how cancer can hijack this vital process and use it for its own benefit. DHX8 plays a role in the final step of splicing, in which genetic information is decoded, and it leads to the production of the diverse forms of protein. Now scientists explore how human DHX8 performs this feat. They also describe its structure and what function this structure serves.
Until now, scientists had a limited understanding of certain regions of DHX8’s structure, including the DEAH motif, the “hook loop” and the “hook turn.” Now, however, the team has succeeded in uncovering more information about how they work. Doctor Rob van Montfort, PhD, explained: “Our study has shed new light on the structure and function of a crucial protein involved in the process of alternative splicing, in which genetic information is mixed and matched to create multiple protein molecules from a single gene. By determining the detailed molecular structure of one of the key protein molecules involved in alternative splicing, we have opened up potentially exciting new avenues for cancer treatment. This research provides valuable information about how cancer cells hijack a process in our cells to make them more diverse and enables them to evade treatment.
Going forward, the researchers plan to look at how DHX8 might contribute to rendering cancer more difficult to treat. In doing so, they hope to find a way of blocking DHX8 or similar molecules. This, they suggest, could be a promising strategy against cancer’s spread and its resistance to therapeutic drugs. Beside, cancer is not the only disease that has defects or hijacking mechanism of protein splicing. This process is also impaired in other diseases. One of these is amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease, a severe and fatal neurodegenerative condition. One of the gene involved in the onset of the disease, TDP-43, is indeed an RNA-binding protein and splicing repression is one of its major role inside cells, according to the latest discoveries. And it cooperates with SMN2, the major neuronal protein found originally mutated or defective in the disease.
A lot of work ahead, therefore: with the hope that one single key may open many doors of theraputic opportunitues.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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