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Witnessing the structural evolution of an RNA enzyme

Xavier Portillo, Yu-Ting Huang, View ORCID ProfileRonald R Breaker, View ORCID ProfileDavid P Horning, View ORCID ProfileGerald F Joyce
doi: https://doi.org/10.1101/2021.06.22.449496
Xavier Portillo
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT
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Yu-Ting Huang
2The Salk Institute, La Jolla, CA
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Ronald R Breaker
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT
3Howard Hughes Medical Institute, New Haven, CT
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David P Horning
2The Salk Institute, La Jolla, CA
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  • For correspondence: dhorning@salk.edu gjoyce@salk.edu
Gerald F Joyce
2The Salk Institute, La Jolla, CA
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  • For correspondence: dhorning@salk.edu gjoyce@salk.edu
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Abstract

An RNA polymerase ribozyme that has been the subject of extensive directed evolution efforts has attained the ability to synthesize complex functional RNAs, including a full-length copy of its own evolutionary ancestor. During the course of evolution, the catalytic core of the ribozyme has undergone a major structural rearrangement, resulting in a novel tertiary structural element that lies in close proximity to the active site. Through a combination of site-directed mutagenesis, structural probing, and deep sequencing analysis, the trajectory of evolution was seen to involve the progressive stabilization of the new structure, which provides the basis for improved catalytic activity of the ribozyme. Multiple paths to the new structure were explored by the evolving population, converging upon a common solution. Tertiary structural remodeling of RNA is known to occur in nature, as evidenced by the phylogenetic analysis of extant organisms, but this type of structural innovation had not previously been observed in an experimental setting. Despite prior speculation that the catalytic core of the ribozyme had become trapped in a narrow local fitness optimum, the evolving population has broken through to a new fitness locale, suggesting that further improvement of polymerase activity may be achievable.

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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 22, 2021.
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Witnessing the structural evolution of an RNA enzyme
Xavier Portillo, Yu-Ting Huang, Ronald R Breaker, David P Horning, Gerald F Joyce
bioRxiv 2021.06.22.449496; doi: https://doi.org/10.1101/2021.06.22.449496
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Witnessing the structural evolution of an RNA enzyme
Xavier Portillo, Yu-Ting Huang, Ronald R Breaker, David P Horning, Gerald F Joyce
bioRxiv 2021.06.22.449496; doi: https://doi.org/10.1101/2021.06.22.449496

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