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Two modes of Cue2-mediated mRNA cleavage with distinct substrate recognition initiate no-go decay

Release:Jan 6, 2023 Update:Jan 6, 2023
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Professor Toshifumi Inada of the Department of Computational Biology and Medical Sciences in the Graduate School of Frontier Sciences, Institute of Medical Science and School of Science led the research project.

Abstract

Ribosome collisions are recognized by E3 ubiquitin ligase Hel2/ZNF598, leading to RQC (ribosome-associated quality control) and to endonucleolytic cleavage and degradation of the mRNA termed NGD (no-go decay). NGD in yeast requires the Cue2 endonuclease and occurs in two modes, either coupled to RQC (NGDRQC+) or RQC uncoupled (NGDRQC−). This is mediated by an unknown mechanism of substrate recognition by Cue2. Here, we show that the ubiquitin binding activity of Cue2 is required for NGDRQC− but not for NGDRQC+, and that it involves the first two N-terminal Cue domains. In contrast, Trp122 of Cue2 is crucial for NGDRQC+. Moreover, Mbf1 is required for quality controls by preventing +1 ribosome frameshifting induced by a rare codon staller. We propose that in Cue2-dependent cleavage upstream of the collided ribosomes (NGDRQC−), polyubiquitination of eS7 is recognized by two N-terminal Cue domains of Cue2. In contrast, for the cleavage within collided ribosomes (NGDRQC+), the UBA domain, Trp122 and the interaction between Mbf1 and uS3 are critical.

Article

Publication:
Nucleic Acids Research (Dec 30, 2022)

Title:
Two modes of Cue2-mediated mRNA cleavage with distinct substrate recognition initiate no-go decay

Authors:
Shota Tomomatsu#, Atsuya Watanabe#, Petr Tesina, Satoshi Hashimoto, Ken Ikeuchi, Sihan Li, Yoshitaka Matsuo, Roland Beckmann, Toshifumi Inada*

DOI: doi.org/10.1093/nar/gkac1172

URL: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac1172/6965460

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