Origin of life: Transitioning to DNA genomes in an RNA world

The unexpected ability of an RNA polymerase ribozyme to copy RNA into DNA has ramifications for understanding how DNA genomes evolved.
  1. Razvan Cojocaru
  2. Peter J Unrau  Is a corresponding author
  1. Simon Fraser University, Canada

For as long as history has been recorded, humanity has tried to answer the ancient question of our origins. The ‘central dogma’ of molecular biology, first stated by Francis Crick in 1958, represented a major step forward in our efforts to answer this question (Figure 1A; Crick, 1958). In this model, the genetic information stored in DNA is transcribed to produce RNA, which is then translated by the ribosome to produce chains of amino acids. These chains fold to make the proteins that are responsible for almost everything that happens in cells.

The emergence of DNA genomes in the RNA world.

(A) In the central dogma of molecular biology, information flows from DNA (red oval) to RNA (green oval) to protein (blue box). DNA is formed of building blocks called deoxynucleoside triphosphates (dNTPs) and can be replicated (solid looping red arrow); RNA is formed of nucleoside triphosphates (NTPs). Enzymes called reverse transcriptases (RT) enable complementary DNA to be made from the building blocks of RNA (dashed arrow). Blue rectangles represent processes catalyzed by proteins; green rectangles show processes catalyzed by RNA; translation is mediated by an RNA catalyst (green inner rectangle) that has proteins that modulate its activity (blue outline). (B) In the RNA world, ribozymes (RdRp) replicate RNA genomes (solid looping red arrow). Based on the work of Joyce and Samanta, if dNTPs were present in the RNA world, reverse transcriptase ribozymes could have constructed DNA genomes using RNA genomes as a template (straight red arrow). Ribozymes could also have potentially replicated DNA genomes (dashed red arrow).

The flow of information from DNA to RNA to protein is thought to have evolved out of a simpler evolutionary period when genetic information was stored and transmitted solely by RNA molecules. This theory, known as the ‘RNA world hypothesis’, posits that an RNA enzyme or ‘ribozyme’ capable of copying RNA molecules existed early in evolution, and that protein synthesis by the ribosome (which is also an RNA enzyme) evolved out of this system (Figure 1B; Gilbert, 1986; Atkins et al., 2011). The theory, however, is largely silent on how DNA genomes evolved.

In modern metabolism, protein-based enzymes called reverse transcriptases can copy RNA to produce molecules of complementary DNA. Other enzymes can promote the production of DNA nucleotides (the building blocks of DNA molecules) from RNA nucleotides via challenging chemical reactions. So how did the first DNA genomes come to be? There are two possibilities within the framework of the RNA world. In the first, protein enzymes evolved before DNA genomes. In the second, the RNA world contained RNA polymerase ribozymes that were able to produce single-stranded complementary DNA and then convert it into stable double-stranded DNA genomes.

A number of laboratories around the world are trying to build ribozymes that can sustain RNA replication (Wang et al., 2011; Attwater et al., 2013). Recently, David Horning and Gerald Joyce artificially evolved a ribozyme that is capable of copying complex RNAs and amplifying short RNA templates (Horning and Joyce, 2016). Now, in eLife, Joyce and Biswajit Samanta at the Salk Institute demonstrate that this ribozyme is also a reverse transcriptase (Samanta and Joyce, 2017). Feeding DNA nucleotides to this ribozyme enabled it to copy short segments of RNA templates into complementary DNA. This suggests that if an RNA world contained DNA nucleotides, DNA genomes could have been assembled and then presumably replicated by ribozymes.

Whether DNA genomes existed very early in evolution fundamentally rests on whether DNA nucleotides were available in the RNA world. There are plausible routes by which RNA and DNA nucleotides could have been synthesized before life emerged, meaning that they are likely to have been available at the dawn of an RNA world (Ritson and Sutherland, 2014Becker et al., 2016; Kim and Benner, 2017). Likewise, artificially selected ribozymes have been used to synthesize the two types of bases found in RNA nucleotides from simpler precursors, suggesting RNA nucleotides could have been built by early RNA systems (Martin et al., 2015). If DNA precursors were also available early in evolution, then the synthesis of DNA nucleotides by an RNA system appears likely. While this area is currently underexplored experimentally, there appears to be no fundamental reason why DNA nucleotides could not have been abundant quite early in evolution.

Demonstrating that DNA polymerase ribozymes are able to rapidly use such DNA nucleotides would represent a major step forward for the early DNA genome model. While the field of artificial RNA polymerase ribozymes has made rapid strides, their ability to add multiple nucleotides rapidly is still very limited. Current ribozymes are significantly longer and more complex than the sequences that they are able to copy, but to make self-evolving systems, ribozymes need to be able to copy sequences that are longer and more complex than themselves. It will therefore be exciting to see if the techniques that have created such RNA polymerases are also able to evolve DNA polymerase ribozymes that have the potential to make self-replicating systems using DNA and not RNA as a source of genetic material. Such a system would bring us closer to understanding the transition from an RNA world to a type of life that respects the rules of the central dogma of modern biology.

References

  1. Book
    1. Atkins JF
    2. Gesteland RF
    3. Cech TR
    (2011)
    RNA Worlds
    Cold Spring Harbor Laboratory.
    1. Crick FH
    (1958)
    On protein synthesis
    Symposia of the Society for Experimental Biology 12:138–163.

Article and author information

Author details

  1. Razvan Cojocaru

    Razvan Cojocaru is in the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada

    Competing interests
    No competing interests declared
  2. Peter J Unrau

    Peter J Unrau is in the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada

    For correspondence
    punrau@sfu.ca
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1392-6948

Publication history

  1. Version of Record published: November 1, 2017 (version 1)

Copyright

© 2017, Cojocaru et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 16,417
    Page views
  • 787
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Razvan Cojocaru
  2. Peter J Unrau
(2017)
Origin of life: Transitioning to DNA genomes in an RNA world
eLife 6:e32330.
https://doi.org/10.7554/eLife.32330
  1. Further reading

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Karolina Honzejkova, Dalibor Kosek ... Tomas Obsil
    Research Article

    Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells toward apoptosis, differentiation, and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular, and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic interventions for these disorders. Nevertheless, as a multidomain Ser/Thr protein kinase, ASK1 is regulated by a complex mechanism involving dimerization and interactions with several other proteins, including thioredoxin 1 (TRX1). Thus, the present study aims at structurally characterizing ASK1 and its complex with TRX1 using several biophysical techniques. As shown by cryo-EM analysis, in a state close to its active form, ASK1 is a compact and asymmetric dimer, which enables extensive interdomain and interchain interactions. These interactions stabilize the active conformation of the ASK1 kinase domain. In turn, TRX1 functions as a negative allosteric effector of ASK1, modifying the structure of the TRX1-binding domain and changing its interaction with the tetratricopeptide repeats domain. Consequently, TRX1 reduces access to the activation segment of the kinase domain. Overall, our findings not only clarify the role of ASK1 dimerization and inter-domain contacts but also provide key mechanistic insights into its regulation, thereby highlighting the potential of ASK1 protein-protein interactions as targets for anti-inflammatory therapy.

    1. Biochemistry and Chemical Biology
    Jake W Anderson, David Vaisar ... Natalie G Ahn
    Research Article

    Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.