RNA G-quadruplex (rG4) exacerbates cellular senescence by mediating ribosome pausing
image: This study illustrates how persistent mRNA rG4 structures induce ribosome pausing and collisions, leading to proteostasis collapse in senescent cells. The RNA helicase DHX9 acts as a key regulator, unwinding rG4 structures to maintain translation elongation and protein homeostasis. The mechanism highlights rG4-DHX9 as a novel axis contributing to aging and related diseases.
Credit: Haoxian Zhou, Shu Wu, Bin Li, Rongjinlei Zhang, Ying Zou, Mibu Cao, Anhua Xu, Kewei Zheng, Qinghua Zhou, Jia Wang, Jinping Zheng, Jianhua Yang, Yuanlong Ge, Zhanyi Lin, Zhenyu Ju
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:
- rG4 structures accumulate in senescent cells: rG4 levels increase significantly in senescent fibroblasts and aged mice tissues, correlating with translation defects and protein aggregation.
- 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.
- Stabilizing rG4 exacerbates senescence: Pharmacological stabilization of rG4 worsens ribosome pausing, proteostasis imbalance, and accelerates senescence-associated phenotypes.
- DHX9 helicase mitigates rG4-induced defects: DHX9 unwinds rG4 structures and prevents ribosome pausing. Its reduced expression in senescent cells exacerbates translation defects.
- 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).