Nicholson-Shaw Tim, Dowdle Megan E, Ajaj Yasmeen, Perelis Mark, Fulzele Amit, Yeo Gene W, Bennett Eric J, Lykke-Andersen Jens
Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA.
RNA. 2025 Jul 16;31(8):1195-1205. doi: 10.1261/rna.080399.125.
Translation elongation stalls trigger mRNA decay and degradation of the nascent polypeptide via translation-dependent quality control pathways. One such pathway, non-stop mRNA decay (NSD), targets aberrant mRNAs that lack stop codons, for example, due to premature polyadenylation. Here we identify Angel1, a CCR4 deadenylase homolog whose biochemical activity remains poorly defined, as a rate-limiting factor for NSD in human cells. Angel1 associates with mRNA coding regions and proteins involved in ribosome-associated quality control and mRNA decay, consistent with a factor that monitors translation elongation stalls. Depletion of Angel1 causes stabilization of reporter mRNAs that are targeted for NSD by the absence of stop codons, but not an mRNA targeted for nonsense-mediated decay. A conserved catalytic residue of Angel1 is critical for its function in NSD. Our findings identify Angel1 as a human NSD factor and suggest that Angel1 catalytic activity plays a critical role in the NSD pathway.
翻译延伸停滞会通过翻译依赖的质量控制途径引发mRNA降解以及新生多肽的降解。其中一条这样的途径，即无义mRNA降解（NSD），靶向缺乏终止密码子的异常mRNA，例如，由于过早的多聚腺苷酸化。在这里，我们鉴定出Angel1，一种CCR4去腺苷酸化酶同源物，其生化活性仍未明确界定，它是人类细胞中NSD的限速因子。Angel1与mRNA编码区以及参与核糖体相关质量控制和mRNA降解的蛋白质相关联，这与一个监测翻译延伸停滞的因子一致。Angel1的缺失导致因缺乏终止密码子而被靶向NSD的报告mRNA稳定，但不会导致被靶向无义介导降解的mRNA稳定。Angel1的一个保守催化残基对其在NSD中的功能至关重要。我们的研究结果将Angel1鉴定为一种人类NSD因子，并表明Angel1催化活性在NSD途径中起关键作用。
