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Rqc2 levels alter CAT tail composition, function, and toxicity in S. cerevisiae

Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, View ORCID ProfileOnn Brandman
doi: https://doi.org/10.1101/687319
Cole S. Sitron
1Department of Biochemistry, Stanford University, Stanford CA, 94305
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Joseph H. Park
1Department of Biochemistry, Stanford University, Stanford CA, 94305
2Department of Chemical & Systems Biology, Stanford University, Stanford CA, 94305
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Jenna M. Giafaglione
1Department of Biochemistry, Stanford University, Stanford CA, 94305
3Molecular Biology Interdepartmental Program, University of California Los Angeles, Los Angeles CA, 90095
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Onn Brandman
1Department of Biochemistry, Stanford University, Stanford CA, 94305
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  • ORCID record for Onn Brandman
  • For correspondence: onn@stanford.edu
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Abstract

The Ribosome-associated Quality Control (RQC) pathway targets incomplete polypeptides from stalled translation for degradation. The primary route of degradation involves ubiquitylation of ribosome-tethered incomplete polypeptides by the E3 ligase Ltn1. To safeguard cells from Ltn1 failure, the protein Rqc2 directs the ribosome to append incomplete polypeptides with carboxy-terminal alanine and threonine residues (CAT tails) that act as degrons, marking RQC-evading polypeptides for degradation. Ltn1 disruption leads to neurodegeneration in animal models yet how this becomes toxic to cells is unclear. We show here that increased Rqc2 levels alter CAT tail composition and exacerbate the toxicity of Ltn1 failure by driving CAT tail aggregation, which inhibits CAT tail degron activity and disrupts proteostasis. Guanidinium hydrochloride exposure or RNA Polymerase III perturbation reverses these Rqc2-induced effects. Our work demonstrates that increased Rqc2 levels convert CAT tails from degrons into toxic aggregates and that pharmacologic or genetic interventions can reverse this process.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 30, 2019.
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Rqc2 levels alter CAT tail composition, function, and toxicity in S. cerevisiae
Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, Onn Brandman
bioRxiv 687319; doi: https://doi.org/10.1101/687319
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Rqc2 levels alter CAT tail composition, function, and toxicity in S. cerevisiae
Cole S. Sitron, Joseph H. Park, Jenna M. Giafaglione, Onn Brandman
bioRxiv 687319; doi: https://doi.org/10.1101/687319

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