RNA G-quadruplex (rG4) exacerbates cellular senescence by mediating ribosome pausing.

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

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RNA G-quadruplex (rG4) exacerbates cellular senescence by mediating ribosome pausing.

Author: Haoxian ZHOU ¹ ; Shu WU ² ; Bin LI ³ ; Rongjinlei ZHANG ² ; Ying ZOU ² ; Mibu CAO ⁴ ; Anhua XU ² ; Kewei ZHENG ⁵ ; Qinghua ZHOU ⁶ ; Jia WANG ⁷ ; Jinping ZHENG ⁷ ; Jianhua YANG ³ ; Yuanlong GE ² ; Zhanyi LIN ¹ ; Zhenyu JU ²
Author Information

1. Department of Cardiology, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
2. Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
3. School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
4. Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, Guangzhou 510317, China.
5. School of Biomedical Sciences, Hunan University, Changsha 410012, China.
6. Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine and The First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
7. Shanxi Key Laboratory of Aging Mechanism Research and Translational Applications, Changzhi Medical College, Changzhi 046012, China.
Publication Type:Journal Article
Keywords: RNA G-quadruplex; cellular senescence; ribosme pausing
MeSH: G-Quadruplexes; Cellular Senescence; Ribosomes/genetics*; Humans; Animals; Mice; DEAD-box RNA Helicases/genetics*; Protein Biosynthesis; RNA/chemistry*; Neoplasm Proteins
From: Protein & Cell 2025;16(11):953-967
CountryChina
Language:English
Abstract: Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.