Unraveling Cellular Compensation: How Cells Fight Back Against Gene Loss
Some genetic mutations that are expected to completely stop a gene from working surprisingly cause only mild or even no symptoms. Previous research identified that cells can increase the activity of other genes performing similar functions to compensate for the loss of a gene's function.
A new study, published on February 12 in the journal Science by researchers in the lab of Jonathan Weissman at MIT, provides insights into how cells coordinate this compensation response. Cells continuously read instructions stored in DNA, called genes, to produce proteins. They first create temporary messenger RNA (mRNA) copies of these instructions. As part of normal cellular maintenance, cells regularly break down these temporary messages. This process helps regulate gene activity and ensures that old or unnecessary messages do not accumulate. Cells also destroy faulty mRNAs that contain errors, which could produce damaged proteins if used.
Beyond Quality Control: mRNA Cleanup as a Signal
In 2019, external studies suggested that mRNA cleanup could serve as more than just a quality-control check. Researchers showed that when faulty mRNAs are broken down, this process can signal cells to activate a compensation response. These studies also indicated that cells select which backup genes to activate based on how closely they resemble the mRNA being degraded.
mRNA decay occurs in the cytoplasm, outside the nucleus where DNA is stored. Mohamed El-Brolosy, a postdoc in the Weissman Lab and lead author of the study, and colleagues investigated how these two processes in different cellular compartments are connected.
Uncovering the Mechanism: ILF3 and RNA 'Addresses'
The researchers began by investigating a specific gene known to trigger a compensation response when its mRNA is destroyed, leading to increased activity in a closely related gene. To identify the molecules aiding this process, they systematically switched off other genes one at a time.
This led to the discovery of a protein called ILF3. When the gene encoding ILF3 was turned off, cells could no longer increase the activity of the backup gene following mRNA decay. Further investigation identified small RNA fragments, which are left behind when faulty mRNAs are destroyed, as underlying this response. These fragments contain a specific sequence that acts as an "address."
Precision Targeting and Future Therapies
The team proposed that this address guides ILF3 to related backup genes that share the same sequence as the faulty mRNA. Introducing mutations in this specific sequence reduced the cells' compensation response, suggesting that the system relies on precise sequence matching to target the correct backup genes.
Jonathan Weissman, an investigator at the Howard Hughes Medical Institute, stated that this finding indicates a regulated system rather than a generic stress response.
"This finding indicates a regulated system rather than a generic stress response."
The researchers' findings point toward new therapeutic possibilities, where boosting the activity of a related gene could mitigate symptoms of certain genetic diseases. Their work also characterizes a previously less understood layer of gene regulation.