@article{facff8d91a304c1a892cfb09774f75ee,
title = "Translational repression of NMD targets by GIGYF2 and EIF4E2",
abstract = "Translation of messenger RNAs (mRNAs) with premature termination codons produces truncated proteins with potentially deleterious effects. This is prevented by nonsense-mediated mRNA decay (NMD) of these mRNAs. NMD is triggered by ribosomes terminating upstream of a splice site marked by an exon-junction complex (EJC), but also acts on many mRNAs lacking a splice junction after their termination codon. We developed a genome-wide CRISPR flow cytometry screen to identify regulators of mRNAs with premature termination codons in K562 cells. This screen recovered essentially all core NMD factors and suggested a role for EJC factors in degradation of PTCs without downstream splicing. Among the strongest hits were the translational repressors GIGYF2 and EIF4E2. GIGYF2 and EIF4E2 mediate translational repression but not mRNA decay of a subset of NMD targets and interact with NMD factors genetically and physically. Our results suggest a model wherein recognition of a stop codon as premature can lead to its translational repression through GIGYF2 and EIF4E2.",
author = "Boris Zinshteyn and Sinha, {Niladri K.} and Enam, {Syed Usman} and Benjamin Koleske and Rachel Green",
note = "Funding Information: This work was funded by the National Institute of General Medical Sciences [2R37GM059425-14 to R.G.; 5K99GM135450-02, including salary support, to B.Z], Howard Hughes Medical Institute (HHMI, https://www.hhmi.org/) (to R.G., including salary) and the Cystic Fibrosis Foundation (https://www.cff.org/, GREEN16G0). B. Z. was an HHMI fellow of and received salary support from the Damon Runyon Cancer Research Foundation [DRG-2250-16] (https://www. damonrunyon.org/) for most of this study. N.S. is a fellow of and received salary support from the Jane Coffin Childs Memorial Fund for cancer research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Kamena Kostova, Christopher Shoemaker and the laboratory of Andrew Holland, particularly Taylor Anglen, for advice on CRISPR screening. We thank Joodh Waleedh for technical assistance. LSRII flow cytometry and FACS sorting was performed at the Johns Hopkins University School of Medicine Ross flow cytometry core facility with the assistance of Xiaoling Zhang and Dixie Hoyle. Illumina sequencing was performed by the Johns Hopkins Genetic Resources Core Facility under the direction of David Mohr. SMG1i was kindly provided by Robert Bridges Ph.D., Rosalind Franklin University of Medicine and Science, through the Cystic Fibrosis Foundation Chemical Compound Program. Figs 2A and 6D were created with BioRender.com. Publisher Copyright: {\textcopyright} 2021 Zinshteyn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2021",
month = oct,
day = "19",
doi = "10.1371/journal.pgen.1009813",
language = "English (US)",
volume = "17",
journal = "PLoS genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10 October",
}