The collapse of protein homeostasis (proteostasis) is a hallmark of cellular aging. This study demonstrates that ribosome pausing, mediated by RNA G-quadruplex (rG4) structures within coding sequences, is a previously underestimated mechanism contributing to proteostasis collapse and cellular senescence.
Key points of the study include:

1. rG4 structures accumulate in senescent cells: rG4 levels increase significantly in senescent fibroblasts and aged mice tissues, correlating with translation defects and protein aggregation.
2. rG4 causes ribosome pausing: Using ribosome profiling and dual fluorescence reporters, the study shows that rG4 structures impede ribosome elongation, leading to ribosomal collisions and truncated protein products.
3. Stabilizing rG4 exacerbates senescence: Pharmacological stabilization of rG4 worsens ribosome pausing, proteostasis imbalance, and accelerates senescence-associated phenotypes.
4. DHX9 helicase mitigates rG4-induced defects: DHX9 unwinds rG4 structures and prevents ribosome pausing. Its reduced expression in senescent cells exacerbates translation defects.
5. rG4-DHX9 axis as a therapeutic target: Modulating rG4 stability or DHX9 activity may provide novel strategies to delay aging and combat age-related disorders.

This work highlights the regulatory role of rG4 in translation and proteostasis, establishing it as a molecular driver of senescence. The study entitled “ RNA G-quadruplex (rG4) exacerbates cellular senescence by mediating ribosome pausing” was published on Protein & Cell (published on June. 12, 2025).
DOI：https://doi.org/10.1093/procel/pwaf047