核糖体
核糖核酸
生物
DNA损伤
翻译(生物学)
泛素连接酶
蛋白质生物合成
细胞生物学
泛素
RNA结合蛋白
应力颗粒
生物化学
DNA
信使核糖核酸
分子生物学
基因
作者
Shubo Zhao,Jacqueline Cordes,Karolina M Caban,Maximilian J. Götz,Timur Mackens‐Kiani,Anthony J. Veltri,Niladri K. Sinha,Pedro Weickert,S Kaya,Graeme Hewitt,Danny D. Nedialkova,Thomas Fröhlich,Roland Beckmann,Allen R. Buskirk,Rachel Green,Julian Stingele
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-12-01
卷期号:83 (23): 4290-4303.e9
被引量:6
标识
DOI:10.1016/j.molcel.2023.10.012
摘要
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.
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