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The 2',3' cyclic phosphatase Angel1 facilitates mRNA degradation during human ribosome-associated quality control

ABSTRACT: The Ribosome-associated Quality Control (RQC) pathway serves to resolve ribosomes stalled during the translation process and degrade the associated mRNA and nascent polypeptide. Here we identify the 2',3' cyclic phosphatase Angel1 as a rate-limiting factor in this process in human cells. Angel1 associates with proteins of the RQC pathway and with mRNA coding regions, consistent with a factor that monitors the translation process. Depletion of Angel1 causes stabilization of reporter mRNAs that are targeted for RQC by the absence of stop codons, but not an mRNA targeted for nonsense-mediated decay. Angel1 catalytic activity is critical for its function in RQC, as a catalytic inactivating mutation causes loss of RQC function. We also identify N4BP2 as the human RQC endonuclease. Given the biochemical activity of Angel1 as a 2',3' cyclic phosphatase, our observations suggest that a rate-limiting step in RQC-mediated mRNA decay is the resolution of a cyclic phosphate, possibly one generated upon N4BP2 cleavage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199650 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:Maintaining the integrity of nucleic acids is an essential feature of all organisms. Unwanted modification of DNA, if left unrepaired, is deleterious to cellular homeostasis and could have far-reaching consequences that include genomic instability and accumulation of mutations. Similarly, accumulation of damaged RNA has been correlated with various neurodegenerative diseases. Given their inherent reactivity, nucleic acids are susceptible to damage from both endogenous and exogenous reactive oxygen species (ROS) as well as alkylation agents. We have recently begun to address how some of these modifications on mRNA impact the function of the ribosome and in particular the decoding process. We find that most modifications severely change the speed and accuracy of translation. These observations revealed that oxidation of RNA is most likely to stall the ribosome and necessitates the presence of quality-control processes to handle damaged mRNA. To this end, we have uncovered a connection between the process of no-go decay (NGD), which degrades mRNAs that stall translation, and chemical insults. In the absence of key NGD factors in yeast, the levels of damaged mRNA significantly increase and cells are rendered sensitive to oxidizing and alkylation agents. Furthermore, these agents activate ribosome quality control (RQC) of nascent peptides. Deletion of the E3 ligase responsible for the ubiquitination of the nascent peptides resulted in the accumulation of protein aggregates in the presence of oxidizing and alkylating agents. These observations suggest that chemical damage stalls translation, activating NGD and RQC. Interestingly, the addition of nucleic-acids-damaging agents was also found to result in K63-linked ubiquitination of ribosomal proteins. This signaling-mode of ubiquitination precedes DNA-damage marks, indicating that cells respond to RNA damage due to stalled ribosomes before DNA damage. Collectively our data highlights the burden of chemically-damaged mRNA on cellular homeostasis and suggests that organisms evolved ribosome-based mRNA-surveillance processes to rapidly degrade it.

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The 2',3' cyclic phosphatase Angel1 facilitates mRNA degradation during human ribosome-associated quality control

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