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. 2021 Jun 25;12:3965. doi: 10.1038/s41467-021-24046-3

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — a Overview of postulated two-factor authentication model. To grant access to the degradative activities of NMD, at least two consecutive security checks need to be passed. Aberrant translation termination in combination with an enhanced residence time of UPF1 on the mRNA and NMD-activating features (e.g., the presence of a downstream EJC) lead to increasing UPF1 phosphorylation by SMG1 (1st authentication step). Sufficiently phosphorylated UPF1 (p-UPF1) leads to the recruitment of SMG5-SMG7 and consequently enables the endonucleolytic activity of SMG6 (2nd authentication step). Domains and functions of SMG5 and SMG7 required to support NMD are indicated (green = low importance, orange = medium, red = high). b Hypothesis for the potential mechanism of the second authentication step. According to this hypothesis, SMG6 can be bound to p-UPF1 before SMG5-SMG7. The role of SMG5-SMG7 in NMD would be the activation of p-UPF1-bound SMG6.