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A self-replicating ligase ribozyme
Open accessAbstract
A self-replicating molecule directs the covalent assembly of component molecules to form a product that is of identical composition to the parent. When the newly formed product also is able to direct the assembly of product molecules, the self-replicating system can be termed autocatalytic. A self-replicating system was developed based on a ribozyme that catalyzes the assembly of additional copies of itself through an RNA-catalyzed RNA ligation reaction. The R3C ligase ribozyme was redesigned so that it would ligate two substrates to generate an exact copy of itself, which then would behave in a similar manner. This self-replicating system depends on the catalytic nature of the RNA for the generation of copies. A linear dependence was observed between the initial rate of formation of new copies and the starting concentration of ribozyme, consistent with exponential growth. The autocatalytic rate constant was 0.011 min −1 , whereas the initial rate of reaction in the absence of pre-existing ribozyme was only 3.3 × 10 −11 M⋅min −1 . Exponential growth was limited, however, because newly formed ribozyme molecules had greater difficulty forming a productive complex with the two substrates. Further optimization of the system may lead to the sustained exponential growth of ribozymes that undergo self-replication.
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“Gerald Joyce (1956–) and coworkers have been able to produce an RNA ligase capable of self-replication in vitro [118].”
From Opinion: The Key Steps in the Origin of Life to the Formation of the Eukaryotic Cell (2024) · cites this paper as [118]
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Wagner, N., Hochberg, D., Peacock-López, E., Maity, I., & Ashkenasy, G. (2019) · Life · doi:10.3390/life9020045 · Cited by 24
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Wang, L.-J., Wang, H.-X., Jiang, L., & Zhang, C.-Y. (2018) · ACS Sensors · doi:10.1021/acssensors.8b01171 · Cited by 15
Synthetic autocatalysts show organocatalysis of other reactions.
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Exploring the space of self-reproducing ribozymes using generative models
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Target-katalysierte Transferreaktionen fr den signalverstrkten RNA-Nachweis
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“Recently a self-replicating system based on a ligase ribozyme has been constructed (Paul and Joyce 2002) that, at least, at early times exhibits exponential growth.”
BackgroundExploiting recognition-mediated assembly and reactivity in [2]rotaxane formation
Vidonne, A., Kosikova, T., & Philp, D. (2016) · Chemical Science · doi:10.1039/c5sc04805b · Cited by 19
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Mizuuchi, R., & Ichihashi, N. (2023) · Chemical Science · doi:10.1039/d3sc01940c · Cited by 17
Evolution of RNA-Based Networks
Stadler, P. F. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_470 · Cited by 11
“As proof of principle, an RNA ligase ribozyme (Paul and Joyce 2002) was obtained in 2002, the first RNA replicase followed in 2009 (Lincoln and Joyce 2009), and was improved stepwise (Ferretti and Joyce 2013).”
MethodRen, R., Wang, L., Ding, T.-R., & Li, X. (2013) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2013.10.063 · Cited by 14
“The R3C ligase was configured to selfreplicate by joining two RNA molecules to produce another copy of itself, and the catalytic properties of the cross-replicating RNA enzymes were improved by Joyce's group (Lincoln and Joyce, 2009; Paul and Joyce, 2002).”
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Kashiwagi, N., Furuta, H., & Ikawa, Y. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp111 · Cited by 12
“It can be readily imagined that RNA ligation reactions would be more important in the RNA and RNP world (25,63).”
Sood, A., Mandal, P. K., Ottelé, J., Wu, J., Eleveld, M., Hatai, J., Pappas, C. G., Huc, I., & Otto, S. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c09111 · Cited by 18
How Catalytic Order Drives the Complexification of Molecular Replication Networks
Wagner, N., & Ashkenasy, G. (2015) · Israel Journal of Chemistry · doi:10.1002/ijch.201400198 · Cited by 10
Campos, C. M., Lanz‐Mendoza, H., Cime‐Castillo, J., Peralta-Zaragoza, Ó., & Madrid‐Marina, V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26114964 · Cited by 10
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tRNA sequences can assemble into a replicator
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“Several nucleic acid systems that display enzyme-free self-replication have been described (Ekland and Bartel, 1996; Johnston et al., 2001; Paul and Joyce, 2002; Li et al., 2017; Hänle and Richert, 2018; Liu et al., 2018; Mariani et al., 2018; Zhang et al., 2019), and there have been a handful of”
MethodNon-enzymatic recombination of RNA: Ligation in loops
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A stepwise emergence of evolution in the RNA world
Nghe, P. (2025) · FEBS Letters · doi:10.1002/1873-3468.70065 · Cited by 8
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Jin, Y., Mandal, P. K., Wu, J., Kiani, A., Zhao, R., Huc, I., & Otto, S. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c09114 · Cited by 10
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Zorc, S. A., & Roy, R. N. (2024) · RNA Biology · doi:10.1080/15476286.2024.2405757 · Cited by 9
“More recently, Joyce showed that an RNA polymerase ribozyme can synthesize its own precursor [23,31,36].”
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Jacques Demongeot, A., & Henrion‐Caude, A. (2020) · Biology · doi:10.3390/biology9050088 · Cited by 11
Understanding Life: A Bioinformatics Perspective
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“50 Many researchers have also conducted experiments to develop ribozymes with various functions: peptidyl transferase ribozyme, 51 ligase 52,53 and nucleotide synthetase.”
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Olea, C., & Joyce, G. F. (2016) · Molecules · doi:10.3390/molecules21101310 · Cited by 12
“The self-replicating RNA enzyme (E) is an RNA ligase that catalyzes the joining of two RNA substrates (A and B) to form another copy of itself [5,6].”
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Brogioli, D. (2011) · Physical Review E · doi:10.1103/physreve.84.031931 · Cited by 7
Stochastic Emergence of Two Distinct Self-Replicators from a Dynamic Combinatorial Library
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“Many examples of this have been reported based on DNA, 17 RNA, 18,19 peptides, 20,21 as well as completely synthetic molecules.”
An Ansatz for Computational Undecidability in RNA Automata
Svahn, A. J., & Prokopenko, M. (2020) · Artificial Life · doi:10.1162/artl_a_00370 · Cited by 7
“This property was exploited to demonstrate that a redesigned R3C ligase could ligate split copies of itself (Paul and Joyce, 2002), starting an auto-catalytic replication cycle (Paul and Joyce, 2002; Lincoln and Joyce, 2009).”
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Ellington, A. D. (2009) · Nature Chemical Biology · doi:10.1038/nchembio0409-200 · Cited by 11
Active centrum hypothesis: The origin of chiral homogeneity and the RNA-world
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“It is to be noted that a self-replicating ligase ribozyme is redesigned so that it would ligate two substrates (one of these oligomers is a 14-mer) to generate a copy by itself (Paul and Joyce, 2002).”
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Encoding Multiple Reactivity Modes within a Single Synthetic Replicator
Robertson, C. C., Kosikova, T., & Philp, D. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c03527 · Cited by 6
Analysis of supramolecular complex energetics in artificial replicators
Dieckmann, A., & Houk, K. N. (2013) · Chemical Science · doi:10.1039/c3sc51192h · Cited by 7
Self-regulation in a minimal model of chemical self-replication
Lou, S. J., & Peacock-López, E. (2011) · Journal of Biological Physics · doi:10.1007/s10867-011-9252-6 · Cited by 9
“Our parameter selection is based on our analysis of chemical self-replication, where parameters are determined by fitting experimental data published by Paul and Joyce [46] and Lincoln and Joyce [47] for self-replicating ribozymes.”
BackgroundMethodMechanistic studies on acyl‐transferase ribozymes and beyond
Hodgson, D. R. W., & Suga, H. (2003) · Biopolymers · doi:10.1002/bip.10518 · Cited by 6
Opinion: The Key Steps in the Origin of Life to the Formation of the Eukaryotic Cell
Brunk, C. F., & Marshall, C. R. (2024) · Life · doi:10.3390/life14020226 · Cited by 5
“Gerald Joyce (1956–) and coworkers have been able to produce an RNA ligase capable of self-replication in vitro [118] Marshall and Brunk call this phase in the development of life the ‘plus RNA World’ to highlight the fact”
BackgroundEffects of lipid membranes on RNA catalytic activity and stability
Czerniak, T., & Sáenz, J. (2025) · Biology of the Cell · doi:10.1111/boc.202400115 · Cited by 5
“Most ribozymes are capable of maintaining their full catalytic activity without other macromolecules (Kruger et al., 1982; Paul & Joyce, 2002; Horning & Joyce, 2016).”
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“Even when ribozyme sequences have been (and will be) found that indeed catalyse their self-replication [58], they are too error-prone and, what is worse, too deleteriously mutable—only few mutations (replacements of a few nucleotides with others, or deletions) bring their catalytic ability to a…”
BackgroundEvolution of Proliferative Model Protocells Highly Responsive to the Environment
Matsuo, M., Toyota, T., Suzuki, K., & Sugawara, T. (2022) · Life · doi:10.3390/life12101635 · Cited by 6
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“Inspired by biological molecular machines such as kinesin [29], RNA polymerase [30] and self-replicating ribozymes [31], qubots draw energy and information from their surroundings with the purpose of maintaining and processing quantum mechanical non-equilibrium states against the detrimental…”
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Amplification of an RNA ligase ribozyme under alternating temperature conditions
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Cross-chiral exponential amplification of an RNA enzyme
Cochrane, W. G., Bare, G. A. L., Joyce, G. F., & Horning, D. P. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2413668121 · Cited by 4
“To enable more favorable self - replication kinetics, an RNA ligase ribozyme was developed that joins two component RNA fragments to form another copy of itself ( 14 ).”
Self-citationHeat‐Flow‐Driven Nonequilibria for Prebiotic Chemistry
Mast, C. B. (2024) · ChemSystemsChem · doi:10.1002/syst.202400039 · Cited by 7
On the emergence of structural complexity in RNA replicators
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“…scenario is compatible with the hypothesis of an early development of membranes (Chen et al. 2005; Szostak 2012; Adamala and Szostak 2013; O ’ Flaherty et al. 2018) and does not require invoking hybridization on surfaces, or the presence of large self-replicating ribozymes (Paul and Joyce 2002).”
Isomoto, N., Maeda, Y., Tanaka, T., Furuta, H., & Ikawa, Y. (2013) · Journal of Molecular Evolution · doi:10.1007/s00239-012-9536-x · Cited by 4
“A system based on the class R3C ligase ribozyme developed by Joyce and coworkers is the most successful example in this regard reported to date (Paul and Joyce 2002; Kim and Joyce 2004) because the R3C-based system shows self-sustained exponential amplification in both self- and…”
Reconstituting alternative life using the test-bed of cell-free systems
Hofmann, M., Abdo, F., Borkowski, O., & Kushwaha, M. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2024.0293 · Cited by 2
The secret life of RNA and lipids
Czerniak, T., & Sáenz, J. (2025) · RNA Biology · doi:10.1080/15476286.2025.2526903 · Cited by 4
“Moreover, the synthetic RNA World provides an experimental platform for studying the principles underlying the evolution of function in a biochemically naïve context [2,3].”
Traces of a Primitive RNA Ring in Current Genomes
Jacques Demongeot, A. (2025) · Biology · doi:10.3390/biology14050538 · Cited by 4
Autocatalytic assembly of a chimeric aminoacyl-RNA synthetase ribozyme
Radakovic, A., Todisco, M., Mishra, A., & Szostak, J. W. (2025) · Science Advances · doi:10.1126/sciadv.adu3693 · Cited by 3
“The loop-closing ligation reaction requires no template, circumventing the formation of catalytically inactive product-template duplexes, which have plagued most RNA-based autocatalytic systems ( 19 – 21 , 44 , 45 ).”
Steady-state solutions of the templator model in chemical self-replication
Shi, Y., Cao, Q. T., Wu, J., & Jia, Y. (2021) · Journal of Mathematical Chemistry · doi:10.1007/s10910-021-01233-7 · Cited by 3
Re‐Evaluation of a Fulvene‐Based Self‐Replicating Diels–Alder Reaction System
Sevim, İ., Pankau, W. M., & von Kiedrowski, G. (2020) · Chemistry - A European Journal · doi:10.1002/chem.201905594 · Cited by 4
A Dynamic Study of Biochemical Self-Replication
Gijima, D. T., & Peacock-López, E. (2020) · Mathematics · doi:10.3390/math8061042 · Cited by 4
“In the experimental systems of Reberk’s [26–32] and Joyce’s [33,35], the reactant concentrations are in the range of micromolar (µM) to 100 µM.”
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Modelling square-wave pulse regulation
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Implementing Molecular Logic Gates, Circuits, and Cascades Using DNAzymes
Lakin, M. R., Stojanović, M. N., & Stefanović, D. (2016) · Emergence, complexity and computation · doi:10.1007/978-3-319-33921-4_1 · Cited by 4
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Replicator Dynamics in Protocells
Stadler, P. F., & Stadler, B. M. R. (2008) · The MIT Press eBooks · doi:10.7551/mitpress/9780262182683.003.0014 · Cited by 1
“…(Szostak et al., 2001) consists of a vesicle containing an RNA genome that contains an RNA-replicase ribozyme (e.g. an advanced version of the molecule described in (Johnston et al., 2001; Paul & Joyce, 2003; Lawrence & Bartel, 2005)) and a functionality that influences the fitness of the vesicle.”
BackgroundInfluentialAccurate phenotypic self-replication as a necessary cause for biological evolution.
GARTE, S. J. (2024) · Biosystems · doi:10.1016/j.biosystems.2024.105154 · Cited by 2
Chemical oscillations in non-isothermal chemical self-replication
Peacock-López, E. (2023) · Chemical Physics · doi:10.1016/j.chemphys.2023.112010 · Cited by 2
Onset model of mutually catalytic self-replicative systems formed by an assembly of polynucleotides
Sawada, Y., Daigaku, Y., & Toma, K. (2023) · Physical review. E · doi:10.1103/physreve.107.054404 · Cited by 2
Gordon, R., & Mikhailovsky, G. E. (2021) · Wiley eBooks · doi:10.1002/9781119640912.ch11 · Cited by 5
RNA diversification by a self-reproducing ribozyme revealed by deep sequencing and kinetic modelling
Jeancolas, C., Matsubara, Y. J., Vybornyi, M., Lambert, C. N., Blokhuis, A. W. P., Alline, T., Griffiths, A. D., Ameta, S., Krishna, S., & Nghe, P. (2021) · Chemical Communications · doi:10.1039/d1cc02290c · Cited by 12
Bigan, E., Mattelaer, H., & Herdewijn, P. A. (2016) · Journal of Molecular Evolution · doi:10.1007/s00239-016-9733-0 · Cited by 3
Krupska, A. (2015) · Journal of Chemical Sciences · doi:10.1007/s12039-015-0871-5 · Cited by 2
Ligand-Dependent Exponential Amplification of Self-Replicating RNA Enzymes
Olea, C., & Joyce, G. F. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2014.10.030 · Cited by 4
Self-citationBrogioli, D. (2012) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2012.11.010 · Cited by 2
Replicators: Components for Systems Chemistry
Taran, O., & von Kiedrowski, G. (2011) · Wiley eBooks · doi:10.1002/9780470977873.ch12 · Cited by 2
A Clocked DNA-Based Replicator
Yurke, B., & Zhang, D. (2005) · Lecture notes in computer science · doi:10.1007/11493785_38 · Cited by 2
“Zhang Recently a self-replicating system based on a ligase ribozyme has been constructed [30] that, at least, at early times exhibits exponential growth.”
Background13 Bioinspired organic chemistry
Williams, N. H. (2003) · Annual Reports Section B (Organic Chemistry) · doi:10.1039/b212017h · Cited by 2
Autocatalysis and organocatalysis with Kemp's triacid compounds
Rebek, J., Kamioka, S., Ajami, D., Sather, A. C., & Hooley, R. (2010) · Heterocycles · doi:10.3987/com-10-s(e)31 · Cited by 2
Peng, Z., Plum, A. M., Kartha, R., Jacobson, E. M., & Baum, D. (2026) · Journal of Molecular Evolution · doi:10.1007/s00239-026-10323-6 · Cited by 2
“…studies have detected ligase or ligase-like activity in relatively short ribozymes (Bartel and Szostak 1993; Ekland and Bartel 1995; Jaeger et al. 1999; Paul and Joyce 2002; Attwater et al. 2018; Nomura and Yokobayashi 2019; DasGupta et al. 2024; Biswas and DasGupta 2026; Gianni et al. 2026 ).”
Nucleic acid catalysts: From the origin of life to modern applications
Müller, S. (2026) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2026.102666 · Cited by 1
A Recipe to Evolve Complex Life Chemically on Earth
Lei, L., & Burton, Z. F. (2025) · Genes · doi:10.3390/genes16101136 · Cited by 1
“Because processive 5 ′ to 3 ′ ribozyme complementary replication has been somewhat difficult to reproduce in laboratories, perhaps ligation on a template was the mechanism utilized for initial complementary replication [22–26].”
DNA‐Based Replication of Programmable Colloidal Assemblies
van Kesteren, S., Diethelm, P. A., Jung, S., & Isa, L. (2024) · Small · doi:10.1002/smll.202400180 · Cited by 2
How prebiotic complexity increases through Darwinian evolution
Yukawa, K., Mizuuchi, R., & Ichihashi, N. (2023) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2023.100456 · Cited by 1
Ribozyme-phenotype coupling in peptide-based coacervate protocells
Vay, K. L. L., Salibi, E., Ghosh, B., Tang, T., & Mutschler, H. (2022) · bioRxiv · doi:10.1101/2022.10.25.513667 · Cited by 1
Sevim, İ. (2021) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.1c01695 · Cited by 1
Front waves in the early RNA world: The Schlögl model and the logistic growth model
Frank, T. D. (2015) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2015.11.027 · Cited by 1
50 Jahre DNA‐Doppelhelix und Miller‐Experiment
von Kiedrowski, G. (2003) · Nachrichten aus der Chemie · doi:10.1002/nadc.20030510606 · Cited by 1
Metadata
- Authors
- Paul, N., & Joyce, G. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Joyce, Gerald F.
- ORCID
- Joyce, Gerald F.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-09-18
- Volume
- 99
- Issue
- 20
- Pages
- 12733-12740
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC130529
- OpenAlex
- W2053143020
- Cited by
- 264
- References
- 0
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 22 · 2023: 8 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 12 · 2018: 6 · 2017: 10 · 2016: 9 · 2015: 12 · 2014: 11 · 2013: 11 · 2012: 8
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Aeronautics and Space Administration (NAG59386)
- Topics
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Mathematics › Theoretical Computer Science › DNA and Biological Computing
- Keywords
- RNA ligation, autocatalysis, RNA catalysis, exponential growth, RNA self-assembly
- MeSH terms
- Base Sequence, Biochemical Phenomena, Biochemistry, Catalysis, Dose-Response Relationship, Drug, Escherichia coli, Kinetics, Molecular Sequence Data, Polynucleotide Ligases, RNA Ligase (ATP), Sequence Homology, Nucleic Acid, Time Factors, Transcription, Genetic, RNA, Catalytic, Dimerization
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