New insights into a hidden process that protects cells from harmful mutations

Some genetic mutations that are expected to completely stop a gene from working surprisingly cause only mild or even no symptoms. Researchers in previous studies have discovered one reason why: Cells can ramp up the activity of other genes that perform similar functions to make up for the loss of an important gene’s function. A new study published Feb. 12 in the journal Science by researchers in the lab of Jonathan Weissman, an MIT professor of biology and Whitehead Institute for Biomedical Research member, now reveals insights into how cells can coordinate this compensation response.Cells are constantly reading instructions stored in DNA. These instructions, called genes, tell them how to make the many proteins that carry out complex processes needed to sustain life. But first, they need to make a temporary copy of these genetic instructions called messenger RNA, or mRNA.As part of normal maintenance, cells routinely break down these temporary messages. This process helps control gene activity — or how much protein is made from a given gene — and ensures that old or unnecessary messages don’t accumulate. Cells also destroy faulty mRNAs that contain errors. These messages, if used, could produce damaged proteins that clump together and interfere with normal cellular processes.In 2019, external studies suggested that this cleanup could be serving as more than just a quality-control check. Researchers showed that when faulty mRNAs are broken down, this breakdown can signal cells to activate the compensation response. These works also suggested that cells decide which backup genes to turn up based on how closely these genes resemble the mRNA that’s being degraded. But mRNA decay is a process that happens in the cytoplasm, outside the nucleus where DNA, and thereby genes, are stored. So, Mohamed El-Brolosy, a postdoc in the Weissman Lab and lead author of the study, and colleagues wondered how those two processes in different compartments of the cell could be connected. Understanding this mechanism with greater depth could enable development of therapeutics that trigger it in a targeted fashion.The researchers started by investigating a specific gene that scientists know triggers a compensation response when its mRNA is destroyed by causing a closely related gene to become more active. To find out which molecules within the cell aid this process, the researchers systematically switched other genes off, one at a time.That’s when they found a protein called ILF3. When the gene encoding this protein was turned off, cells could no longer ramp up the activity of the backup gene following mRNA decay.Upon further investigation, the researchers identified small RNA fragments — left behind when faulty mRNAs are destroyed — underlying this response. These fragments contain a special sequence that acts like an “address.” The team proposed that this address guides ILF3 to related backup genes that share the same sequence as the faulty mRNA.In fact, when they introduced mutations in this sequence, the cells’ compensation response dropped, suggesting that the system relies on precise sequence matching to target the correct backup genes.“That was very exciting for us,” says Weissman, who is also an investigator at the Howard Hughes Medical Institute. “It showed us that this isn’t a generic stress response. It’s a regulated system.”The researchers’ findings point toward new therapeutic possibilities, where boosting the activity of a related gene could mitigate symptoms of certain genetic diseases. More broadly, their work characterizes a mysterious layer of gene regulation.