Certain genetic mutations that should completely block a gene’s function sometimes cause only minimal or no visible effects. Cells can offset such disruptions through a mechanism called transcriptional adaptation, which increases the activity of related genes that fulfill similar roles. A study led by Jonathan Weissman at the Whitehead Institute clarifies how this compensation occurs by linking the decay of messenger RNA (mRNA) to the activation of substitute genes.
Cells routinely create and destroy mRNAs as part of normal function. These temporary messages carry DNA‑encoded instructions to make proteins, and their continual degradation prevents defective messages from producing harmful or unnecessary proteins. Earlier studies in 2019 suggested that the breakdown of faulty mRNAs does more than serve as simple quality control—the decay products themselves can prompt cells to boost transcription of similar genes, helping to maintain normal function even when a crucial gene is lost.
The new research explores how a signal originating in the cytoplasm, where mRNA degradation occurs, can influence gene activation within the nucleus. Mohamed El‑Brolosy, a postdoctoral researcher in the Weissman Lab and lead author of the study published in Science, used a gene known to trigger compensation after its mRNA is destroyed as a model system. By systematically switching off other genes, the team discovered that the RNA‑binding protein ILF3 is central to this communication pathway. When the gene encoding ILF3 was deactivated, cells could no longer increase the expression of compensatory genes following mRNA decay.
Further investigation showed that small RNA fragments generated during mRNA breakdown act as triggers in the process. These fragments contain short sequence motifs functioning as molecular “addresses,” guiding ILF3 to genes that contain matching sequences and can serve as backups for the lost gene. When researchers introduced mutations that altered these sequences, the compensatory response weakened, indicating that accurate sequence recognition is essential for transcriptional adaptation to work effectively.
“This isn’t a generic stress response. It’s a regulated system,” Weissman noted.
Publication details: Mohamed A. El-Brolosy et al., Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation. Science391, eaea 1272 (2026). DOI:10.1126/science.aea1272
Cells routinely create and destroy mRNAs as part of normal function. These temporary messages carry DNA‑encoded instructions to make proteins, and their continual degradation prevents defective messages from producing harmful or unnecessary proteins. Earlier studies in 2019 suggested that the breakdown of faulty mRNAs does more than serve as simple quality control—the decay products themselves can prompt cells to boost transcription of similar genes, helping to maintain normal function even when a crucial gene is lost.
The new research explores how a signal originating in the cytoplasm, where mRNA degradation occurs, can influence gene activation within the nucleus. Mohamed El‑Brolosy, a postdoctoral researcher in the Weissman Lab and lead author of the study published in Science, used a gene known to trigger compensation after its mRNA is destroyed as a model system. By systematically switching off other genes, the team discovered that the RNA‑binding protein ILF3 is central to this communication pathway. When the gene encoding ILF3 was deactivated, cells could no longer increase the expression of compensatory genes following mRNA decay.
Further investigation showed that small RNA fragments generated during mRNA breakdown act as triggers in the process. These fragments contain short sequence motifs functioning as molecular “addresses,” guiding ILF3 to genes that contain matching sequences and can serve as backups for the lost gene. When researchers introduced mutations that altered these sequences, the compensatory response weakened, indicating that accurate sequence recognition is essential for transcriptional adaptation to work effectively.
“This isn’t a generic stress response. It’s a regulated system,” Weissman noted.
Publication details: Mohamed A. El-Brolosy et al., Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation. Science391, eaea 1272 (2026). DOI:10.1126/science.aea1272
Comment