Design and Experimental Evolution of trans-Splicing Group I Intron Ribozymes

Müller, Ulrich F.

doi:10.3390/molecules22010075

Cited by 20 publications

(26 citation statements)

References 78 publications

(143 reference statements)

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“…Likewise, those ALPHA-derived pentamers were present in the D Chain of many hairpin ribozymes. This remnant presence of motifs could have been used to build simple RNA "cells", consisting of two ribozymes with concerted activity allowing RNA replication [67][68][69][70][71][72].…”

Section: Alpha Remnants In Different Living Realmsmentioning

confidence: 99%

Footprints of a Singular 22-Nucleotide RNA Ring at the Origin of Life

Demongeot

Henrion‐Caude

2020

Biology

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(1) Background: Previous experimental observations and theoretical hypotheses have been providing insight into a hypothetical world where an RNA hairpin or ring may have debuted as the primary informational and functional molecule. We propose a model revisiting the architecture of RNA-peptide interactions at the origin of life through the evolutionary dynamics of RNA populations. (2) Methods: By performing a step-by-step computation of the smallest possible hairpin/ring RNA sequences compatible with building up a variety of peptides of the primitive network, we inferred the sequence of a singular docosameric RNA molecule, we call the ALPHA sequence. Then, we searched for any relics of the peptides made from ALPHA in sequences deposited in the different public databases. (3) Results: Sequence matching between ALPHA and sequences from organisms among the earliest forms of life on Earth were found at high statistical relevance. We hypothesize that the frequency of appearance of relics from ALPHA sequence in present genomes has a functional necessity. (4) Conclusions: Given the fitness of ALPHA as a supportive sequence of the framework of all existing theories, and the evolution of Archaea and giant viruses, it is anticipated that the unique properties of this singular archetypal ALPHA sequence should prove useful as a model matrix for future applications, ranging from synthetic biology to DNA computing.

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Section: Alpha Remnants In Different Living Realmsmentioning

confidence: 99%

Footprints of a Singular 22-Nucleotide RNA Ring at the Origin of Life

Demongeot

Henrion‐Caude

2020

Biology

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“…The spliceosome and self‐splicing group II intron ribozymes share a common ancestor, suggesting that a ribozyme similar to today's self‐splicing group II introns performed analogous functions to today's spliceosomes. There are some reports in the literature on the engineering of spliceozymes based on the even simpler structure of group I introns . However, earlier stages of the RNA world may have relied on even simpler RNA structures than those of group I introns to mediate RNA splicing.…”

Section: Self‐splicing Hairpin Ribozyme Variantsmentioning

confidence: 99%

“…There are some reports in the literature on the engineering of spliceozymes based on the even simpler structure of group I introns. [47][48][49][50] However, earlier stages of the RNA world may have relied on even simpler RNA structures than those of group I introns to mediate RNA splicing. As described above, the hairpin ribozyme can efficiently support both phosphodiester bond cleavage and ligation and therefore again is a perfect candidate for a simple ancient spliceozyme.…”

Section: Regular Splicingmentioning

confidence: 99%

Engineering of hairpin ribozyme variants for RNA recombination and splicing

Hieronymus¹,

Müller²

2019

Annals of the New York Academy of Sciences

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The hairpin ribozyme is a small, naturally occurring RNA that catalyzes the reversible cleavage of RNA substrates. Among the small endonucleolytic ribozymes, the hairpin ribozyme possesses the unique feature of the internal equilibrium between cleavage and ligation being shifted toward ligation. This allows control of the reaction outcome by structural design: fragments that are strongly bound to the ribozyme are preferentially ligated, whereas substrates that easily dissociate upon cleavage, such that they are not available for religation, are preferentially cleaved. We have made use of this characteristic feature in engineering a number of hairpin ribozyme variants by programmed conformational design that carry out cascades of cleavage and ligation reactions, and as a result mediate more complex RNA processing reactions. Here, we review our work on the engineering of hairpin ribozyme variants for RNA recombination and regular and back‐splicing, and discuss the relevance of such activities in early life.

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“…Moreover, an approximate six base‐pair increase in the P10 helix can increase the 3′‐splice site specificity; however, the optimal length of this increase differs among splice sites (Kohler et al, ; Suh & Waring, ). Recently, selection (Ayre, Kohler, Turgeon, & Haseloff, ; Beaudry & Joyce, ; Hasegawa, Choi, & Rao, ; Hayden, Ferrada, & Wagner, ; Ohuchi, Ikawa, Shiraishi, & Inoue, ; Olson & Muller, ; Treiber, Rook, Zarrinkar, & Williamson, ) and evolution (Amini & Muller, ; Olson, Dolan, & Muller, ; Zhao, Giver, Shao, Affholter, & Arnold, ) methods have been used to identify and develop trans ‐splicing ribozymes with improved activity (for a detailed review on these methods in Muller, ). These two methods, which do not require the individual generation and testing of many ribozyme constructs, can greatly facilitate the development of improved trans ‐splicing ribozymes.…”

Section: Group I Intron Ribozymesmentioning

confidence: 99%

Therapeutic applications of group I intron‐based trans‐splicing ribozymes

2018

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Since the breakthrough discovery of catalytic RNAs (ribozymes) in the early 1980s, valuable ribozyme-based gene therapies have been developed for incurable diseases ranging from genetic disorders to viral infections and cancers. Ribozymes can be engineered and used to downregulate or repair pathogenic genes via RNA cleavage mediated by trans-cleaving ribozymes or repair and reprograming mediated by trans-splicing ribozymes, respectively. Uniquely, trans-splicing ribozymes can edit target RNAs via simultaneous destruction and repair (and/or reprograming) to yield the desired therapeutic RNAs, thus selectively inducing therapeutic gene activity in cells expressing the target RNAs. In contrast to traditional gene therapy approaches, such as simple addition of therapeutic transgenes or inhibition of disease-causing genes, the selective repair and/or reprograming abilities of trans-splicing ribozymes in target RNA-expressing cells facilitates the maintenance of endogenous spatial and temporal gene regulation and reduction of disease-associated transcript expression. In molecular imaging technologies, trans-splicing ribozymes can be used to reprogram specific RNAs in living cells and organisms by the 3'-tagging of reporter RNAs. The past two decades have seen progressive improvements in trans-splicing ribozymes and the successful application of these elements in gene therapy and molecular imaging approaches for various pathogenic conditions, such as genetic, infectious, and malignant disease. This review provides an overview of the current status of trans-splicing ribozyme therapeutics, focusing on Tetrahymena group I intron-based ribozymes, and their future prospects. This article is categorized under: RNA in Disease and Development > RNA in Disease.

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Design and Experimental Evolution of trans-Splicing Group I Intron Ribozymes

Cited by 20 publications

References 78 publications

Footprints of a Singular 22-Nucleotide RNA Ring at the Origin of Life

Footprints of a Singular 22-Nucleotide RNA Ring at the Origin of Life

Engineering of hairpin ribozyme variants for RNA recombination and splicing

Therapeutic applications of group I intron‐based trans‐splicing ribozymes

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