RNA Backbone Methylation Occurs Under Hypoxic Conditions! : Stereoselective RNA Methylation Activates Ribosomes

The ribosome is a highly structured ribonucleoprotein complex that functions as the protein synthesizer of the cell. Traditionally, ribosomes were thought to have a fixed composition and structure. However, in recent years, the concept of “specialized ribosomes,” whose composition changes in response to environmental conditions to optimize their activity, has attracted growing attention. The research team led by Project Research Associate Kensuke Ishiguro and Prof. Tsutomu Suzuki from the University of Tokyo’s School of Engineering focused on the possibility that ribosome function is modulated through alterations in rRNA modifications when organisms adapt to anaerobic environments.

Under anaerobic growth conditions in Escherichia coli, they discovered an increased level of 5-hydroxycytidine at position 2501 (ho⁵C2501), as well as the appearance of two novel methylations at positions 2449 and 2498 within the peptidyl transferase center (PTC) of 23S rRNA. NMR analysis revealed that these methylations possess unprecedented chemical structures, in which methyl groups are stereoselectively introduced into the RNA sugar-phosphate backbone. These modifications were designated 5ʹ(S)-dihydrouridine (D^5Sm2449) and 2ʹ-O-5ʹ(S)-dimethylcytidine (Cm^5Sm2498), respectively.

Furthermore, biochemical and structural analyses showed that these hypoxia-induced modifications stabilize the PTC structure and enhance ribosomal activity. The modifications were also found to be essential for sustaining bacterial growth under anaerobic conditions. These findings demonstrate that ribosomes are activated by hypoxia-induced rRNA modifications, thereby enhancing translational capacity and promoting survival in low-oxygen environments.

This study uncovers a previously unknown mechanism by which RNA modifications sense cellular growth conditions and regulate protein synthesis. It also has the potential to serve as a valuable technological platform for cell-free protein synthesis and synthetic biology.

Papers

Journal: Molecular Cell

Title: Hypoxia-induced ribosomal RNA modifications in the peptidyl-transferase center contribute to anaerobic growth of bacteria

Authors: Kensuke Ishiguro, Karin Midorikawa, Naoki Shigi, Satoshi Kimura, Aivar Liiv, Takeshi Yokoyama, Takuhiro Ito, Mikako Shirouzu, Jaanus Remme, Kenjyo Miyauchi, and Tsutomu Suzuki*

* Corresponding author

DOI: 10.1016/j.molcel.2025.11.018