RT Journal Article
SR Electronic
T1 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 792994
DO 10.1101/792994
A1 Kelsey L. Hickey
A1 Kimberley Dickson
A1 J. Zachery Cogan
A1 Joseph M. Replogle
A1 Michael Schoof
A1 Karole N. D’Orazio
A1 Niladri K. Sinha
A1 Adam Frost
A1 Rachel Green
A1 Jonathan S. Weissman
A1 Kamena K. Kostova
YR 2020
UL http://biorxiv.org/content/early/2020/05/19/792994.abstract
AB 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 the degradation of the faulty mRNA and partially synthesized polypeptide. Here, we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific silencing of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Their recruitment to defective messages can be mediated by different factors, including potentially the collision sensor ZNF598. Both 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.Competing Interest StatementThe authors have declared no competing interest.