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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4290-4303.e9
JournalMOLECULAR CELL
Volume83
Issue number23
Early online date2 Nov 2023
DOIs
Publication statusPublished - 7 Dec 2023

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