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

Abstract

SummaryThe 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 for 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 findings suggest that a rate-limiting step in RQC-mediated mRNA decay is the resolution of a cyclic phosphate, possibly one generated upon N4BP2 cleavage.