Rxivist logo

GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control

By Kelsey L Hickey, Kimberley Dickson, J. Zachery Cogan, Joseph M Replogle, Michael Schoof, Karole N. D’Orazio, Niladri K Sinha, Adam Frost, Rachel Green, Jonathan S. Weissman, Kamena K Kostova

Posted 03 Oct 2019
bioRxiv DOI: 10.1101/792994 (published DOI: 10.1016/j.molcel.2020.07.007)

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 Statement The authors have declared no competing interest.

Download data

  • Downloaded 1,628 times
  • Download rankings, all-time:
    • Site-wide: 8,209 out of 118,130
    • In genetics: 430 out of 5,131
  • Year to date:
    • Site-wide: 5,619 out of 118,130
  • Since beginning of last month:
    • Site-wide: 27,714 out of 118,130

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News