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Ribozymes02:47

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The term ribozyme is used for RNA that can act as an enzyme. Ribozymes are mainly found in selected viruses, bacteria, plant organelles, and lower eukaryotes. Ribozymes were first discovered in 1982 when Tom Cech’s laboratory observed Group I introns acting as enzymes. This was shortly followed by the discovery of another ribozyme, Ribonulcease P, by Sid Altman’s laboratory. Both Cech and Altman received the Nobel Prize in chemistry in 1989 for their work on ribozymes.
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A cross-chiral RNA polymerase ribozyme.

Jonathan T Sczepanski1, Gerald F Joyce1

  • 1Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Nature
|November 4, 2014
PubMed
Summary

Researchers developed a novel cross-chiral RNA polymerase that overcomes chiral inhibition, enabling the replication of both D- and L-RNA molecules. This breakthrough addresses a key challenge in understanding the origin of RNA-based life.

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Area of Science:

  • Origin of Life Studies
  • Molecular Biology
  • Biochemistry

Background:

  • Template-directed polymerization of activated mononucleotides is inhibited by opposing enantiomers, posing a challenge for early RNA-based life.
  • The emergence of RNA enzymes (ribozymes) capable of catalyzing RNA polymerization is crucial for RNA replication and evolution.
  • It was previously assumed that early RNA polymerases and their substrates shared the same chirality (handedness).

Purpose of the Study:

  • To investigate the possibility of cross-chiral RNA replication, where an RNA enzyme of one handedness can polymerize substrates of the opposite handedness.
  • To engineer a functional cross-chiral RNA polymerase using in vitro evolution.
  • To demonstrate that RNA-based life could have emerged from a system with broken chiral symmetry.

Main Methods:

  • In vitro evolution was employed, starting with a diverse population of random-sequence RNA molecules.
  • Selection pressure was applied to identify RNA sequences that could catalyze the polymerization of non-native chiral substrates.
  • The catalytic activity and substrate specificity of the evolved RNA enzymes were characterized.

Main Results:

  • An 83-nucleotide D-RNA enzyme was evolved that efficiently catalyzes the templated polymerization of L-RNA substrates.
  • A complementary L-RNA enzyme was also developed, demonstrating similar cross-chiral catalytic activity with D-RNA substrates.
  • Chiral inhibition was circumvented as the evolved enzymes exhibit significant rate acceleration exclusively for cross-chiral substrates (up to 10^6-fold).
  • The cross-chiral RNA polymerase demonstrated the ability to synthesize full-length RNA copies of its own enantiomer.

Conclusions:

  • Cross-chiral RNA polymerases can be evolved, providing a plausible mechanism for overcoming chiral inhibition in the origin of RNA-based life.
  • The emergence of D- and L-RNA replication systems may have occurred concurrently, facilitated by cross-chiral catalysis.
  • This finding supports the hypothesis that chiral symmetry could be broken through chemical processes, paving the way for RNA evolution.