@article{52177e3c138442899e748d423f8ffdb5,
title = "RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks",
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.",
author = "Shubo Zhao and Jacqueline Cordes and Caban, {Karolina M} and G{\"o}tz, {Maximilian J} and Timur Mackens-Kiani and Veltri, {Anthony J} and Sinha, {Niladri K} and Pedro Weickert and Selay Kaya and Graeme Hewitt and Nedialkova, {Danny D} and Thomas Fr{\"o}hlich and Roland Beckmann and Buskirk, {Allen R} and Rachel Green and Julian Stingele",
note = "Funding Information: We thank F. Schleich for preliminary work on this study. We also thank the Core Facility Flow Cytometry at Biomedical Center, LMU Munich and SFB 1361 at Institute Molecular Biology, Mainz for experimental support. S.Z. was supported by the LMU – China Scholarship Council Program and J.C. and P.W. by the International Max-Planck Research School for Molecular Life Sciences. Research in the lab of J.S. is supported by the European Research Council (ERC Starting Grant 801750 DNAProteinCrosslinks); Alfried Krupp Prize for Young University Teachers awarded by Alfried-Krupp von Bohlen und Halbach Stiftung, European Molecular Biology Organization (YIP4644); The Vallee Foundation; and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project ID 213249687—SFB 1064, project ID 393547839—SFB 1361). G.H. is supported by the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990), A.R.B. by the National Institutes of Health (grant GM136960), and R.G. by Howard Hughes Medical Institute. D.D.N. is funded by the Max Planck Society, the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (ERC Starting grant no. 803825-TransTempoFold), and SFB 1035 (German Research Foundation DFG, Sonderforschungsbereich 1035, Projektnummer 201302640, project B14). Conceptualization, S.Z. J.C. and J.S.; investigation, S.Z. J.C. K.M.C. T.M.-K. A.J.V. N.K.S. and S.K.; resources, P.W. and G.H.; formal analysis, M.J.G. and A.R.B.; funding acquisition, J.S. R.G. R.B. T.F. D.D.N. and G.H.; supervision, J.S. R.G. R.B. T.F. and D.D.N.; writing – original draft, S.Z. J.C. and J.S.; writing – review & editing, S.Z. J.C. K.M.C. M.J.G. T.M.-K. N.K.S. P.W. G.H. T.F. R.B. A.R.B. R.G. and J.S. R.G. is a member of the scientific advisory board at the journal Molecular Cell. Funding Information: We thank F. Schleich for preliminary work on this study. We also thank the Core Facility Flow Cytometry at Biomedical Center, LMU Munich and SFB 1361 at Institute Molecular Biology, Mainz for experimental support. S.Z. was supported by the LMU – China Scholarship Council Program and J.C. and P.W. by the International Max-Planck Research School for Molecular Life Sciences . Research in the lab of J.S. is supported by the European Research Council (ERC Starting Grant 801750 DNAProteinCrosslinks); Alfried Krupp Prize for Young University Teachers awarded by Alfried-Krupp von Bohlen und Halbach Stiftung , European Molecular Biology Organization ( YIP4644 ); The Vallee Foundation ; and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project ID 213249687— SFB 1064 , project ID 393547839— SFB 1361 ). G.H. is supported by the Radiation Research Unit at the Cancer Research UK City of London Centre Award ( C7893/A28990 ), A.R.B. by the National Institutes of Health (grant GM136960 ), and R.G. by Howard Hughes Medical Institute . D.D.N. is funded by the Max Planck Society , the European Research Council under the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (ERC Starting grant no. 803825 -TransTempoFold), and SFB 1035 ( German Research Foundation DFG, Sonderforschungsbereich 1035, Projektnummer 201302640, project B14). Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = dec,
day = "7",
doi = "10.1016/j.molcel.2023.10.012",
language = "English",
volume = "83",
pages = "4290--4303.e9",
journal = "MOLECULAR CELL",
issn = "1097-2765",
publisher = "Cell Press",
number = "23",
}