衝突するリボソームがRNA修復を活性化する(Colliding ribosomes activate RNA repair)

2023-11-11

2023-11-10 ミュンヘン大学(LMU)

◆体内でアルコール摂取などの代謝過程で生成されるアルデヒドは有毒で、DNAやRNA、タンパク質などの細胞構成要素に結合して損傷を与える。DNAの損傷は細胞が修復するが、以前はRNAのクロスリンク損傷がどのように感知され修復されるかは不明だった。
◆ミュンヘンのチームは、RNAのクロスリンク損傷がタンパク質合成を妨げることを明らかにし、リボソームがこの損傷を検知して修復する新たなメカニズムを見つけた。DNAを損傷する化合物が細胞のバランスに影響を与え、抗がん剤の作用メカニズムにも関連することが示された。

<関連情報>

RNF14依存的な非定型ユビキチン化がRNA-タンパク質架橋の翻訳連鎖解消を促進する RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks

Shubo Zhao,Jacqueline Cordes,Karolina M. Caban,Maximilian J. Götz,Timur Mackens-Kiani,Anthony J. Veltri,Niladri K. Sinha,Pedro Weickert,Selay Kaya,Graeme Hewitt,Danny D. Nedialkova,Thomas Fröhlich,Roland Beckmann,Allen R. Buskirk,Rachel Green,Julian Stingele
Molecular Cell Published:November 09, 2023
DOI:https://doi.org/10.1016/j.molcel.2023.10.012

Highlights

•Photoactivatable ribonucleoside-enhanced crosslinking is used to study RNA damage
•RNA crosslinking damage triggers translation stress
•Crosslinks between proteins and mRNAs are resolved in a translation-coupled manner
•Resolution requires atypical ubiquitylation of the protein adduct by RNF14

Summary

Reactive aldehydes are abundant endogenous metabolites that challenge homeostasis by crosslinking cellular macromolecules. Aldehyde-induced DNA damage requires repair to prevent cancer and premature aging, but it is unknown whether cells also possess mechanisms that resolve aldehyde-induced RNA lesions. Here, we establish photoactivatable ribonucleoside-enhanced crosslinking (PAR-CL) as a model system to study RNA crosslinking damage in the absence of confounding DNA damage in human cells. We find that such RNA damage causes translation stress by stalling elongating ribosomes, which leads to collisions with trailing ribosomes and activation of multiple stress response pathways. Moreover, we discovered a translation-coupled quality control mechanism that resolves covalent RNA-protein crosslinks. Collisions between translating ribosomes and crosslinked mRNA-binding proteins trigger their modification with atypical K6- and K48-linked ubiquitin chains. Ubiquitylation requires the E3 ligase RNF14 and leads to proteasomal degradation of the protein adduct. Our findings identify RNA lesion-induced translational stress as a central component of crosslinking damage.