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Review
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The Origins of the RNA World

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Review

The Origins of the RNA World

Michael P Robertson et al. Cold Spring Harb Perspect Biol.

Abstract

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 reconcile 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.

Figures

Figure 1.
Figure 1.
Phosphodiester linkages resulting from chemical condensation of nucleotides. (A) Reaction of an activated mononucleotide (Ni+1) with an oligonucleotide (N1–Ni ) to form a 3′,5′-phosphodiester (left), 2′,5′-phosphodiester (middle), or 5′,5′-pyrophosphate linkage (right). (B) Typical oligomeric product resulting from chemical condensation of activated mononucleotides.
Figure 2.
Figure 2.
Nonenzymatic synthesis of multi-stem-loop structures as a result of untemplated (open arrowhead) and templated (filled arrowhead) reactions. Template-directed synthesis is assumed to occur rapidly whenever a template, activated monomers, and a suitable primer are available. Once the complementary strand is completed, additional residues are added slowly in a random-sequence manner.
Figure 3.
Figure 3.
Nucleophilic attack by the 3′-hydroxyl of a template-bound oligonucleotide (N1–Ni) on the α-phosphorus of an adjacent template-bound mononucleotide (Ni+1). Dotted lines indicate base pairing to a complementary template. R is the leaving group.
Figure 4.
Figure 4.
X-ray crystal structure of the (A) L1 ligase and (B) class I ligase ribozymes. Insets show the putative magnesium ion binding sites at the respective ligation junctions. The structures are rendered in rainbow continuum, with the 5′-triphosphate-bearing end of the ribozyme colored violet and the 3′-hydroxyl-bearing end of the substrate colored red. The phosphate at the ligation junction is shown in white, and the proximate magnesium ion (modeled for the class I ligase) is shown as a yellow sphere, with dashed lines indicating coordination contacts.
Figure 5.
Figure 5.
Known RNA-catalyzed reactions that are relevant to nucleotide biosynthesis. (A) Formation of 4-thiouridylate from free 4-thiouracil and ribozyme-tethered 5-phosphoribosyl-1-pyrophosphate. (B) 5′-phosphorylation of an oligonucleotide using γ-thio-ATP as the phosphate donor. (C) Activation of a nucleoside 5′-phosphate by formation of a 5′,5′-pyrophosphate linkage. (D) Template-directed ligation of RNA driven by release of a 5′,5′-pyrophosphate-linked adenylate.
Figure 6.
Figure 6.
Potential prebiotic synthesis of pyrimidine nucleosides. (A) Reaction of ribose with cyanamide to form a bicyclic product, with cyanamide joined at both the anomeric carbon and 2-hydroxyl. (B) Analogous reaction of arabinose-3-phosphate to form a bicyclic product, which then reacts with cyanoacetylene to form a tricyclic intermediate that hydrolyzes to give a mixture of cytosine arabinoside-3′-phosphate and cytosine 2′,3′-cyclic phosphate. (C) Reaction of glycoaldehyde with cyanamide in neutral phosphate buffer, followed by addition of glyceraldehyde, to form ribose and arabinose amino-oxazoline (and lesser amounts of the xylose and lyxose compounds). Arabinose amino-oxazoline then reacts with cyanoacetylene to give cytosine 2′,3′-cyclic phosphate as the major product.
Figure 7.
Figure 7.
The structures of (A) RNA; (B) p-RNA; (C) TNA; (D) GNA; (E) PNA; (F) ANA; (G) diaminotriazine-tagged (left) and dioxo-5-aminopyrimidine-tagged (right) oligodipeptides; and (H) tPNA. ANA contains a backbone of alternating d- and l-alanine subunits. The diaminotriazine tags are shown linked to a backbone of alternating l-aspartate and l-glutamate subunits; the dioxo-5-aminopyrimidine tags (shown unattached) can be linked similarly. tPNA is shown with a backbone of alternating l-cysteine and l-glutamate subunits.

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