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

Area of Science:

• Molecular Biology
• Cellular Biology
• Aging Research

Background:

• Loss of protein homeostasis is a key feature of cellular senescence.
• Ribosome pausing significantly contributes to the collapse of proteostasis during senescence.
• The specific role of ribosome pausing in senescent cells requires further elucidation.

Purpose of the Study:

• To investigate the impact of RNA G-quadruplexes (rG4s) on translation efficiency in senescent cells.
• To explore the role of rG4 structures and their regulators in cellular senescence and aging.

Main Methods:

• Ribosome profiling to assess translation efficiency.
• G-quadruplex RNA immunoprecipitation sequencing (RIP-seq) to map rG4 structures.
• In vivo and in vitro translation assays.
• Analysis of DHX9 expression in senescent cells and aged mice.

Main Results:

• Translation efficiency of rG4-rich genes is reduced in senescent cells.
• rG4 structures within coding sequences impede translation.
• Increased rG4 abundance and stabilization exacerbate cellular senescence.
• Reduced DHX9 expression in senescent cells leads to increased ribosome pausing.
• Aged mice exhibit increased rG4, impaired proteostasis, and reduced DHX9.

Conclusions:

• rG4 structures play a significant role in regulating translation and proteostasis during cellular senescence.
• DHX9 is a key regulator of rG4 abundance, impacting ribosome pausing.
• Targeting rG4s and DHX9 may offer strategies to delay cellular senescence and aging.