Healthcare (Commonwealth Union) – Researchers from the Indian Institute of Science (IISc) recently revealed how a protein synthesis glitch may play a key role tumor growth. They pointed out that as protein synthesis, also known as translation occurs, the genetic code carried by mRNA is used to assemble amino acids, which are the fundamental units of proteins. As the translation apparatus moves along the mRNA, it reads the nucleotide sequence in groups of three called codons, with each codon specifying a particular amino acid.
Some codons signal where the translation process should begin and end. However, occasionally, the machinery bypasses a stop codon, leading to the production of a longer-than-intended protein. This phenomenon is referred to as stop codon read-through.
Sandeep Eswarappa, Associate Professor at the Department of Biochemistry, IISc indicated that as the additional segment in the protein can alter its location within the cell, its stability, or even its function.
In a recent study published in the Journal of Cell Science, Eswarappa’s research group focused on a gene responsible for producing a protein called FEM1B. Their findings highlight how FEM1B mRNA read-through plays a crucial role in regulating the cell cycle, with significant implications for cancer cell growth and tumor development.
The FEM1B protein was said to be a component of a complex responsible for tagging other proteins for degradation, ensuring that the correct proteins are targeted. This complex regulates crucial proteins involved in various cellular processes, including the cell cycle, to control cell proliferation.
In the research, scientists discovered that stop codon read-through results in the production of a longer, less stable form of FEM1B, which ironically signals FEM1B for degradation, reducing its levels. The team identified a specific nucleotide sequence at the end of the FEM1B gene that guides this read-through.
Having a inquisitive mind about how this impacts cancer cell growth—a key feature of cancer being uncontrolled cell division—the researchers used the CRISPR-Cas9 system, a widely used gene-editing tool, to remove the sequence responsible for read-through from the FEM1B gene in lab-grown cancer cells. Blocking the read-through led to higher FEM1B protein levels, increasing the degradation of targeted proteins and slowing down the cell cycle, which in turn reduced the proliferation of cancer cells.
“This was surprising, as it brought a clinical relevance to this study,” explained lead author Md Noor Akhtar, who is an Integrated PhD student in the Eswarappa lab. Researchers then proceeded to inject the read-through-defective cancer cell lines in a mice model and discovered that the consequent tumours grew with less pace.
Analyzing publicly accessible datasets from human cancer patients, the researchers found that higher expression of the FEM1B gene was linked to better survival rates, supporting their hypothesis.
When examining the evolutionary history of the FEM1B gene, they discovered that the readthrough process appears to be unique to humans and chimpanzees. They believe this issue may have arisen from the insertion of a single nucleotide just after the first stop codon—a small change that likely occurred around 10 million years ago, when humans and chimpanzees diverged from other primates. The researchers speculate that this mutation might have contributed to humans’ increased vulnerability to cancer compared to other primates.
Eswarappa’s team indicated that they continue to be confused by how exactly the stop codon readthrough takes place. They had expressed their woillingness to finding out the molecular machinery taking place, which will assist in making any therapeutic approach more specific. He added “If we know the mechanism, we can target and regulate the readthrough process, which in turn might help in controlling the tumour progression.”
The finding may play significant role for cancer researchers to understand the mechanism of tumors.
