The Origins of the RNA World

Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press The Origins of the RNA World Michael P. Robertson and Gerald F. Joyce Departments of Chemistry and Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037 Correspondence: [email protected] SUMMARY The general notion of an “RNA World” is that, in the early development of life on the Earth, genetic continuity was assured by the replication of RNA and genetically encoded proteins were not involved as catalysts. There is now strong evidence indicating that an RNA World did indeed exist before DNA- and protein-based life. However, arguments regarding whether life on Earth began with RNA are more tenuous. It might be imagined that all of the components of RNA were available in some prebiotic pool, and that these components assembled into replicating, evolving polynucleotides without the prior existence of any evolved macromolecules. A thorough consideration of this “RNA-first” view of the origin of life must recon- cile concerns regarding the intractable mixtures that are obtained in experiments designed to simulate the chemistry of the primitive Earth. Perhaps these concerns will eventually be resolved, and recent experimental findings provide some reason for optimism. However, the problem of the origin of the RNA World is far from being solved, and it is fruitful to consider the alternative possibility that RNA was preceded by some other replicating, evolving molecule, just as DNA and proteins were preceded by RNA. Outline 1 Introduction 4 Concluding remarks 2 An “RNA-first” view of the origin of life References 3 An “RNA-later” view of the origin of life Editors: John F. Atkins, Raymond F. Gesteland, and Thomas R. Cech Additional Perspectives on RNA Worlds available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003608 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press M.P. Robertson and G.F. Joyce 1 INTRODUCTION and recent experimental findings provide some reason for optimism. However, the problem of the origin of the RNA The general idea that, in the development of life on the World is far from being solved, and it is fruitful to consider Earth, evolution based on RNA replication preceded the the alternative possibility that RNA was preceded by some appearance of protein synthesis was first proposed over other replicating, evolving molecule, just as DNA and pro- 40 yr ago (Woese1967; Crick 1968; Orgel 1968). It was sug- teins were preceded by RNA. gested that catalysts made entirely of RNA are likely to have been important at this early stage in the evolution of life, 2 AN “RNA-FIRST” VIEW OF THE ORIGIN OF LIFE but the possibility that RNA catalysts might still be present Abiotic Synthesis of Polynucleotides in contemporary organisms was overlooked. The unantici- pated discovery of ribozymes (Kruger et al. 1982; Guerrier- This section considers the synthesis of oligonucleotides 0 Takada et al. 1983) initiated extensive discussion of the role from ß-D-nucleoside 5 -phosphates, leaving aside for now of RNA in the origins of life (Sharp 1985; Pace and Marsh the question of how the nucleotides became available on 1985; Lewin 1986) and led to the coining of the phrase “the the primitive Earth. Two fundamentally different chemical RNAWorld” (Gilbert 1986). reactions are involved. First, the nucleotide must be con- “The RNA World” means different things to different verted to an activated derivative, for example, a nucleoside investigators, so it would be futile to attempt a restrictive 50-polyphosphate. Next the 30-hydroxyl group of a nucleo- definition. All RNA World hypotheses include three basic tide or oligonucleotide molecule must be made to react assumptions: (1) At some time in the evolution of life, with the activated phosphate group of a monomer. Synthe- genetic continuity was assured by the replication of RNA; sis of oligonucleotides from nucleoside 30-phosphates will (2) Watson-Crick base-pairing was the key to replication; not be discussed because activated nucleoside 20-or (3) genetically encoded proteins were not involved as cata- 30-phosphates in general react readily to form 20,30-cyclic lysts. RNA World hypotheses differ in what they assume phosphates. These cyclic phosphates are unlikely to oligo- about life that may have preceded the RNA World, about merize efficiently because the equilibrium constant for the metabolic complexity of the RNA World, and about dimer formation is only of the order of 1.0 L/mol (Erman the role of small-molecule cofactors, possibly including and Hammes 1966; Mohr and Thach 1969). In the presence peptides, in the chemistry of the RNAWorld. of a complementary template somewhat larger oligomers There is now strong evidence indicating that an RNA might be formed because the free energy of hybridization World did indeed exist on the early Earth. The smoking would help to drive forward the chain extension reaction. gun is seen in the structure of the contemporary ribosome In enzymatic RNA and DNA synthesis, the nucleoside (Ban et al. 2000; Wimberly et al. 2000; Yusupov et al. 2001). 50-triphosphates (NTPs) are the substrates of polymeriza- The active site for peptide-bond formation lies deep within tion. Polynucleotide phosphorylase, although it is a deg- a central core of RNA, whereas proteins decorate the out- radative enzyme in nature, can be used to synthesize side of this RNA core and insert narrow fingers into it. oligonucleotides fromnucleoside50-diphosphates. Nucleo- No amino acid side chain comes within 18 A˚ of the active side 50-polyphosphates are, therefore, obvious candidates site (Nissen et al. 2000). Clearly, the ribosome is a ribozyme for the activated forms of nucleotides. Although nucleoside (Steitz and Moore 2003), and it is hard to avoid the conclu- 50-triphosphates are not formed readily, the synthesis of nu- sion that, as suggested by Crick, “the primitive ribosome cleoside 50-tetraphosphates from nucleotides and inorganic could have been made entirely of RNA” (1968). trimetaphosphate provides a reasonably plausible prebiotic Amoretenuousargumentcanbemaderegarding route to activated nucleotides (Lohrmann 1975). Other whether life on Earth began with RNA. In what has been re- more or less plausible prebiotic syntheses of nucleoside ferred to as “The Molecular Biologist’s Dream” (Joyce and 50-polyphosphates from nucleotides have also been re- Orgel 1993), one might imagine that all of the components ported (Handschuh et al. 1973; Osterberg et al. 1973; Reim- of RNAwere available in some prebiotic pool, and that these ann and Zubay 1999). Less clear, however, is how the first components could have assembled into replicating, evolving phosphate would have been mobilized to convert the nu- polynucleotides without the prior existence of any evolved cleosides to 50-nucleotides. Nucleoside 50-polyphosphates macromolecules. However, a thorough consideration of are high-energy phosphate esters, but are relatively unreac- this “RNA-first” view of the origin of life inevitably triggers tive in aqueous solution. This may be advantageous for “The Prebiotic Chemist’s Nightmare”,with visions of the in- enzyme-catalyzed polymerization, but is a severe obstacle tractable mixtures that are obtained in experiments designed for the nonenzymatic polymerization of nucleoside 50-pol- to simulate the chemistryof the primitive Earth. Perhaps this yphosphates, which would occur far more slowly than the continuing nightmare will eventually have a happy ending, hydrolysis of the resulting polynucleotide. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003608 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Origins of the RNA World In a different approach to the activation of nucleotides, and30,50-phosphodiester-linkedadducts(Fig.1A),inorderof the isolation of an activated intermediate is avoided by decreasing abundance (Sulston et al. 1968). Thusthe conden- using a condensing agent such as a carbodiimide (Khorana sation of several monomers would likely yield an oligomer 1961). This is a popular method in organic synthesis, containing one pyrophosphate and a preponderance of but its application to prebiotic chemistry is problematic. 20,50-phosphodiester linkages (Fig. 1B). There is little chance Potentially prebiotic molecules such as cyanamide and of producing entirely 30,50-linked oligomers from activated cyanoacetylene activate nucleotides in aqueous solution, nucleotides unless a catalyst can be found that increases the but the subsequent condensation reactions are inefficient proportion of 30,50-phosphodiester linkages. Several metal 2+ 2+ (Lohrmann and Orgel 1973). ions, particularly Pb and UO2 , catalyze the formation of Most attempts to study nonenzymatic polymerization oligomers fromnucleoside 50-phosphorimidazolides(Sleeper of nucleotides in the context of prebiotic chemistry have and Orgel 1979; Sawai et al. 1988). The Pb2+-catalyzed reac- used nucleoside 50-phosphoramidates, particularly nucleo- tion is especially efficient when performed in eutectic solu- side 50-phosphorimidazolides. Although phosphorimida- tions of the activated monomers (in concentrated

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