‘Turning the Textbook on Its Head’: First Evidence of Phosphate Backbone Modification in RNA

It has been confirmed for the first time that RNA molecules can undergo chemical modifications not only to their bases or ribose, but also to their phosphate backbone.

According to BioOn on the 17th (local time), a team led by Professor Shurag Schwartz at the Weizmann Institute of Science in Israel reported the discovery of a naturally occurring thiophosphate (PS) modification in the RNA phosphate backbone in a study published in the international journal Cell.

More than 150 chemical modifications are known in RNA, but most occur in the bases or ribose. The phosphate backbone has been considered an unmodified region.

The PS modification replaces one oxygen atom in a phosphate group with sulfur. It is widely used in RNA therapeutics to increase resistance to nucleases and improve stability.

The research team developed a method combining sequencing and mass spectrometry to detect PS modifications in RNA at the single-nucleotide level. Using this method, they reliably identified PS modification sites in ribosomal RNA (rRNA) and transfer RNA (tRNA) from several archaea.

The modification was not fixed but varied with environmental sulfur concentration and temperature. The team suggested that it may be a regulatory mechanism that helps archaea adapt to extreme environments.

The team also identified a group of enzymes that cause PS modifications. These enzymes selectively modified tRNA or rRNA, and the presence or absence of the enzymes corresponded with the distribution of PS modifications.

Removing these enzymes caused the archaea to die or become sensitive to temperature. PS modifications in tRNA were found to increase tRNA stability, confirming that the modifications are not incidental but have a physiological function.

This discovery provides the first evidence that natural RNA can also be modified in its phosphate backbone, expanding the chemical scope of RNA modifications. However, the findings to date are limited to archaea, and whether the modifications occur in eukaryotes and humans has yet to be determined.

The team said that because PS modification is already a mature technology in RNA therapeutics, archaeal enzymes could serve as tools for stereospecific modification and help develop more efficient and precise methods for synthesizing RNA medicines.