Oxidation and alkylation stresses activate ribosome-quality control

• Published in: Nature communications 2019-12, Vol.10 (1), p.5611-15, Article 5611
• Main Authors: Yan, Liewei L., Simms, Carrie L., McLoughlin, Fionn, Vierstra, Richard D., Zaher, Hani S.
• Format: Article
• Language: English
• Subjects: 13/109; 4-Nitroquinoline-1-oxide - metabolism; 45/90; 631/337/1645/1769; 631/45/500; 82/1; 82/29; 82/51; 82/58; Accumulation; Alkylating agents; Alkylation; Bases (nucleic acids); Biological evolution; Chemical damage; Clonal deletion; Damage accumulation; DNA Adducts - metabolism; DNA Damage; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Methyl Methanesulfonate - pharmacology; mRNA; multidisciplinary; Mutation - genetics; Organic chemistry; Oxidation; Oxidation-Reduction; Oxidative Stress; Peptides - metabolism; Polyribosomes - metabolism; Protein Aggregates; Proteins; Quality control; Quinolones - metabolism; Ribosomal proteins; Ribosomal Proteins - metabolism; Ribosomes - drug effects; Ribosomes - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Science; Science (multidisciplinary); Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13579-3

Oxidation and alkylation of nucleobases are known to disrupt their base-pairing properties within RNA. It is, however, unclear whether organisms have evolved general mechanism(s) to deal with this damage. Here we show that the mRNA-surveillance pathway of no-go decay and the associated ribosome-quality control are activated in response to nucleobase alkylation and oxidation. Our findings reveal that these processes are important for clearing chemically modified mRNA and the resulting aberrant-protein products. In the absence of Xrn1, the level of damaged mRNA significantly increases. Furthermore, deletion of LTN1 results in the accumulation of protein aggregates in the presence of oxidizing and alkylating agents. This accumulation is accompanied by Hel2-dependent regulatory ubiquitylation of ribosomal proteins. Collectively, our data highlight the burden of chemically damaged mRNA on cellular homeostasis and suggest that organisms evolved mechanisms to counter their accumulation. The mRNA-surveillance pathway of no-go decay (NGD) is a eukaryotic ribosome-based-quality-control process that targets transcripts that stall the ribosome. Here the authors show no-go decay (NGD) and ribosome-quality control (RQC) pathways are activated by mRNAs damaged by alkylation and oxidation stress.