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A shape-shifting nuclease unravels structured RNA

View ORCID ProfileKatarina Meze, View ORCID ProfileArmend Axhemi, Dennis R. Thomas, Ahmet Doymaz, View ORCID ProfileLeemor Joshua-Tor
doi: https://doi.org/10.1101/2021.11.30.470623
Katarina Meze
1W.M. Keck Structural Biology Laboratory, Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, 11724, USA
2Cold Spring Harbor School of Biological Sciences
3Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
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  • ORCID record for Katarina Meze
Armend Axhemi
1W.M. Keck Structural Biology Laboratory, Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, 11724, USA
3Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
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Dennis R. Thomas
1W.M. Keck Structural Biology Laboratory, Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, 11724, USA
3Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
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Ahmet Doymaz
2Cold Spring Harbor School of Biological Sciences
4Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA
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Leemor Joshua-Tor
1W.M. Keck Structural Biology Laboratory, Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, 11724, USA
2Cold Spring Harbor School of Biological Sciences
3Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
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  • For correspondence: leemor@cshl.edu
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Abstract

RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts that may otherwise interfere with cellular programs. The enzyme Dis3-like protein 2 (Dis3L2) is a 3’-5’ exoribonuclease that, through its RNA turnover activity, plays a critical role in human development1. Dis3L2 can independently degrade structured substrates and its targets include many coding and non-coding 3’-uridylated RNAs1–5. While the basis for Dis3L2’s substrate recognition has been well-characterized6, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining electron cryo-microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for single-stranded (ss) and double-stranded (ds) RNA processing. We discovered a dramatic conformational change that is triggered by the dsRNA, involving repositioning of two cold shock domains by 70 Å. This movement exposes a trihelix-linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not ssRNA, degradation. These findings reveal the conformational plasticity of this enzyme, and detail a novel mechanism of structured RNA degradation.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 30, 2021.
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A shape-shifting nuclease unravels structured RNA
Katarina Meze, Armend Axhemi, Dennis R. Thomas, Ahmet Doymaz, Leemor Joshua-Tor
bioRxiv 2021.11.30.470623; doi: https://doi.org/10.1101/2021.11.30.470623
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A shape-shifting nuclease unravels structured RNA
Katarina Meze, Armend Axhemi, Dennis R. Thomas, Ahmet Doymaz, Leemor Joshua-Tor
bioRxiv 2021.11.30.470623; doi: https://doi.org/10.1101/2021.11.30.470623

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