@article{1848397a36ab406494f9c57dcaf0adff,
title = "GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control",
abstract = "Ribosome-associated quality control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs. Extensive work in yeast has identified highly conserved mechanisms that lead to degradation of faulty mRNA and partially synthesized polypeptides. Here we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific inhibition of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function.",
author = "Hickey, {Kelsey L.} and Kimberley Dickson and Cogan, {J. Zachery} and Replogle, {Joseph M.} and Michael Schoof and D'Orazio, {Karole N.} and Sinha, {Niladri K.} and Hussmann, {Jeffrey A.} and Marco Jost and Adam Frost and Rachel Green and Weissman, {Jonathan S.} and Kostova, {Kamena K.}",
note = "Funding Information: We thank M. Shurtleff and A. Mizrak for scientific input and helpful discussions, R. Pak and P. Solomon for help with genetic screens, K. Popova for advice regarding knockout cell line generation, and G. Ow and E. Collisson for sharing the mCherry-marked sgRNA expression vector. This work was supported by the NIH Center for RNA Systems Biology (to J.S.W.), NIH Directors{\textquoteright} Early Independence Award 1DP5OD028147-01 (to K.K.K.), a UCSF Genentech fellowship (to K.L.H.), an HHMI faculty scholar award (to A.F.), and NIH grants 5R01AG041826-05 (to J.S.W.) and K99 GM130964 (to M.J.). J.A.H. is the Rebecca Ridley Kry Fellow of the Damon Runyon Cancer Research Foundation ( DRG-2262-16 ). A.F. is a Chan Zuckerberg Biohub investigator. J.S.W and R.G. are Howard Hughes Medical Institute Investigators. Funding Information: We thank M. Shurtleff and A. Mizrak for scientific input and helpful discussions, R. Pak and P. Solomon for help with genetic screens, K. Popova for advice regarding knockout cell line generation, and G. Ow and E. Collisson for sharing the mCherry-marked sgRNA expression vector. This work was supported by the NIH Center for RNA Systems Biology (to J.S.W.), NIH Directors{\textquoteright} Early Independence Award 1DP5OD028147-01 (to K.K.K.), a UCSF Genentech fellowship (to K.L.H.), an HHMI faculty scholar award (to A.F.), and NIH grants 5R01AG041826-05 (to J.S.W.) and K99 GM130964 (to M.J.). J.A.H. is the Rebecca Ridley Kry Fellow of the Damon Runyon Cancer Research Foundation (DRG-2262-16). A.F. is a Chan Zuckerberg Biohub investigator. J.S.W and R.G. are Howard Hughes Medical Institute Investigators. K.K.K. K.D. K.L.H. A.F. and J.S.W. conceived the study. K.L.H. K.K.K. and J.S.W. wrote the manuscript with input from all authors. K.L.H. K.K.K. K.D. J.M.R. J.Z.C. M.S. K.N.D. and N.K.S. performed all experiments. M.J. contributed to the genetic interaction experiments. M.J. J.A.H. and J.M.R. performed data analyses. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = sep,
day = "17",
doi = "10.1016/j.molcel.2020.07.007",
language = "English (US)",
volume = "79",
pages = "950--962.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}