The RNA World and the Origins of Life Molecular Biology of the Cell

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

NCBI Book sh elf. A ser v ice of t h e Na t ion a l Libr a r y of Medicin e, Na t ion a l In st it u t es of Hea lt h .

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New Y ork: Garland
Science; 2002.

The RNA World and the Origins of Life
To fully understand the processes occurring in present-day living cells, we need to consider how they arose in evolution. The most fundamental of all such problems is the expression of hereditary information, which today requires extraordinarily complex machinery and proceeds from DNA to protein through an RNA intermediate. How did this machinery arise? One view is that an RNA world existed on Earth before modern cells arose (Figure 6-91). According to this hypothesis, RNA stored both genetic information and catalyzed the chemical reactions in primitive cells. Only later in evolutionary time did DNA take over as the genetic material and proteins become the major catalyst and structural component of cells. If this idea is correct, then the transition out of the RNA world was never complete; as we have seen in this chapter, RNA still catalyzes several fundamental reactions in modern-day cells, which can be viewed as molecular fossils of an earlier world.
Figure 6-91

Time line for the universe, suggesting the early existence of an
RNA world of living systems.
In this section we outline some of the arguments in support of the RNA world hypothesis. We will see that several of the more surprising features of modern-day cells, such as the ribosome and the premRNA splicing machinery, are most easily explained by viewing them as descendants of a complex network of RNA-mediated interactions that dominated cell metabolism in the RNA world. We also discuss how DNA may have taken over as the genetic material, how the genetic code may have arisen, and how proteins may have eclipsed RNA to perform the bulk of biochemical catalysis in modern-day cells. Life Requires Autocatalysis
It has been proposed that the first “biological” molecules on Earth were formed by metal-based catalysis on the crystalline surfaces of minerals. In principle, an elaborate system of molecular synthesis and breakdown (metabolism) could have existed on these surfaces long before the first cells arose. But life requires molecules that possess a crucial property: the ability to catalyze reactions that lead, directly or indirectly, to the production of more molecules like themselves. Catalysts with this special selfpromoting property can use raw materials to reproduce themselves and thereby divert these same materials from the production of other substances. But what molecules could have had such autocatalytic properties in early cells? In present-day cells the most versatile catalysts are polypeptides, composed of many different amino acids with chemically diverse side chains and, consequently, able to adopt diverse three-dimensional forms that bristle with reactive chemical groups. But, although polypeptides are versatile as catalysts, there is no known way in which one such molecule can reproduce itself by directly specifying the formation of another of precisely the same sequence.
Polynucleotides Can Both Store Information and Catalyze Chemical Reactions
Polynucleotides have one property that contrasts with those of polypeptides: they can directly guide the formation of exact copies of their own sequence. This capacity depends on complementary base pairing of nucleotide subunits, which enables one polynucleotide to act as a template for the formation of http://www.ncbi.nlm.nih.gov/books/NBK26876/ 1/8

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

another. As we have seen in this and the preceding chapter, such complementary templating mechanisms lie at the heart of DNA replication and transcription in modern-day cells.
But the efficient synthesis of polynucleotides by such complementary templating mechanisms requires catalysts to promote the polymerization reaction: without catalysts, polymer formation is slow, errorprone, and inefficient. Today, template-based nucleotide polymerization is rapidly catalyzed by protein enzymes—such as the DNA and RNA polymerases. How could it be catalyzed before proteins with the appropriate enzymatic specificity existed? The beginnings of an answer to this question were obtained in
1982, when it was discovered that RNA molecules themselves can act as catalysts. We have seen in this chapter, for example, that a molecule of RNA is the catalyst for the peptidyl transferase reaction that takes place on the ribosome. The unique potential of RNA molecules to act both as information carrier and as catalyst forms the basis of the RNA world hypothesis.
RNA therefore has all the properties required of a molecule that could catalyze its own synthesis (Figure
6-92). Although self-replicating systems of RNA molecules have not been found in nature, scientists are hopeful that they can be constructed in the laboratory. While this demonstration would not prove that self-replicating RNA molecules were essential in the origin of life on Earth, it would certainly suggest that such a scenario is possible.
Figure 6-92

An RNA molecule that can catalyze its own synthesis. This hypothetical process would require catalysis of the production of both a second RNA strand of complementary nucleotide sequence and the use of this second RNA molecule as a template to form many (more...)
A Pre-RNA World Probably Predates the RNA World
Although RNA seems well suited to form the basis for a self-replicating set of biochemical catalysts, it is unlikely that RNA was the first kind of molecule to do so. From a purely chemical standpoint, it is difficult to imagine how long RNA molecules could be formed initially by purely nonenzymatic means.
For one thing, the precursors of RNA, the ribonucleotides, are difficult to form nonenzymatically.
Moreover, the formation of RNA requires that a long series of 3′ to 5′ phosphodiester linkages form in the face of a set of competing reactions, including hydrolysis, 2′ to 5′ linkages, 5′ to 5′ linkages, and so on. Given these problems, it has been suggested that the first molecules to possess both catalytic activity and information storage capabilities may have been polymers that resemble RNA but are chemically simpler (Figure 6-93). We do not have any remnants of these compounds in present-day cells, nor do such compounds leave fossil records. Nonetheless, the relative simplicity of these “RNA-like polymers” make them better candidates than RNA itself for the first biopolymers on Earth that had both information storage capacity and catalytic activity.
Figure 6-93

Structures of RNA and two related information-carrying polymers. In each case, B indicates the positions of purine and pyrimidine bases. The polymer p-RNA (pyranosyl-RNA) is RNA in which the furanose (five-membered ring) form of ribose has been replaced (more...)
The transition between the pre-RNA world and the RNA world would have occurred through the http://www.ncbi.nlm.nih.gov/books/NBK26876/ 2/8

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

synthesis of RNA using one of these simpler compounds as both template and catalyst. The plausibility of this scheme is supported by laboratory experiments showing that one of these simpler forms (PNA— see Figure 6-93) can act as a template for the synthesis of complementary RNA molecules, because the overall geometry of the bases is similar in the two molecules. Presumably, pre-RNA polymers also catalyzed the formation of ribonucleotide precursors from simpler molecules. Once the first RNA molecules had been produced, they could have diversified gradually to take over the functions originally carried out by the pre-RNA polymers, leading eventually to the postulated RNA world.
Single-stranded RNA Molecules Can Fold into Highly Elaborate Structures
We have seen that complementary base-pairing and other types of hydrogen bonds can occur between nucleotides in the same chain, causing an RNA molecule to fold up in a unique way determined by its nucleotide sequence (see, for example, Figures 6-6, 6-52, and 6-67). Comparisons of many RNA structures have revealed conserved motifs, short structural elements that are used over and over again as parts of larger structures. Some of these RNA secondary structural motifs are illustrated in Figure 694. In addition, a few common examples of more complex and often longer-range interactions, known as RNA tertiary interactions, are shown in Figure 6-95.
Figure 6-94

Common elements of RNA secondary structure. Conventional, complementary base-pairing interactions are indicated by red
“rungs” in double-helical portions of the RNA.
Figure 6-95

Examples of RNA tertiary interactions. Some of these interactions can join distant parts of the same RNA molecule or bring two separate RNA molecules together.
Protein catalysts require a surface with unique contours and chemical properties on which a given set of substrates can react (discussed in Chapter 3). In exactly the same way, an RNA molecule with an appropriately folded shape can serve as an enzyme (Figure 6-96). Like some proteins, many of these ribozymes work by positioning metal ions at their active sites. This feature gives them a wider range of catalytic activities than can be accounted for solely by the limited chemical groups of the polynucleotide chain. Figure 6-96

This simple RNA molecule catalyzes the cleavage of a second RNA at a specific site.
This ribozyme is found embedded in larger RNA genomes—called viroids—which infect plants. The cleavage, which occurs in nature at a distant location on (more...)

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Relatively few catalytic RNAs exist in modern-day cells, however, and much of our inference about the
RNA world has come from experiments in which large pools of RNA molecules of random nucleotide sequences are generated in the laboratory. Those rare RNA molecules with a property specified by the experimenter are then selected out and studied (Figure 6-97). Experiments of this type have created
RNAs that can catalyze a wide variety of biochemical reactions (Table 6-4), and suggest that the main difference between protein enzymes and ribozymes lies in their maximum reaction speed, rather than in the diversity of the reactions that they can catalyze.
Figure 6-97

Beginning with a large pool of nucleic acid molecules synthesized in the laboratory, those rare RNA molecules that possess a specified catalytic activity can be isolated and studied. Although a specific example (that of an autophosphorylating (more...)

Table 6-4

Some Biochemical Reactions That Can Be Catalyzed by
Ribozymes.
Like proteins, RNAs can undergo allosteric conformational changes, either in response to small molecules or to other RNAs. One artificially created ribozyme can exist in two entirely different conformations, each with a different catalytic activity (Figure 6-98). Moreover, the structure and function of the rRNAs in the ribosome alone have made it clear that RNA is an enormously versatile http://www.ncbi.nlm.nih.gov/books/NBK26876/ 4/8

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

molecule. It is therefore easy to imagine that an RNA world could reach a high level of biochemical sophistication. Figure 6-98

An RNA molecule that folds into two different ribozymes. This
88-nucleotide RNA, created in the laboratory, can fold into a ribozyme that carries out a self-ligation reaction (left) or a selfcleavage reaction (right). The ligation reaction forms a 2′,5′
(more...)
Self-Replicating Molecules Undergo Natural Selection
The three-dimensional folded structure of a polynucleotide affects its stability, its actions on other molecules, and its ability to replicate. Therefore, certain polynucleotides will be especially successful in any self-replicating mixture. Because errors inevitably occur in any copying process, new variant sequences of these polynucleotides will be generated over time.
Certain catalytic activities would have had a cardinal importance in the early evolution of life. Consider in particular an RNA molecule that helps to catalyze the process of templated polymerization, taking any given RNA molecule as a template. (This ribozyme activity has been directly demonstrated in vitro, albeit in a rudimentary form that can only synthesize moderate lengths of RNA.) Such a molecule, by acting on copies of itself, can replicate. At the same time, it can promote the replication of other types of
RNA molecules in its neighborhood (Figure 6-99). If some of these neighboring RNAs have catalytic actions that help the survival of RNA in other ways (catalyzing ribonucleotide production, for example), a set of different types of RNA molecules, each specialized for a different activity, may evolve into a cooperative system that replicates with unusually great efficiency.
Figure 6-99

A family of mutually supportive RNA molecules, one catalyzing the reproduction of the others.

One of the crucial events leading to the formation of effective self-replicating systems must have been the development of individual compartments. For example, a set of mutually beneficial RNAs (such as those of Figure 6-99) could replicate themselves only if all the RNAs were to remain in the neighborhood of the RNA that is specialized for templated polymerization. Moreover, if these RNAs were free to diffuse among a large population of other RNA molecules, they could be co-opted by other replicating systems, which would then compete with the original RNA system for raw materials.
Selection of a set of RNA molecules according to the quality of the self-replicating systems they generated could not occur efficiently until some form of compartment evolved to contain them and thereby make them available only to the RNA that had generated them. An early, crude form of compartmentalization may have been simple adsorption on surfaces or particles.
The need for more sophisticated types of containment is easily fulfilled by a class of small molecules that has the simple physicochemical property of being amphipathic, that is, consisting of one part that is hydrophobic (water insoluble) and another part that is hydrophilic (water soluble). When such molecules are placed in water they aggregate, arranging their hydrophobic portions as much in contact with one http://www.ncbi.nlm.nih.gov/books/NBK26876/ 5/8

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

another as possible and their hydrophilic portions in contact with the water. Amphipathic molecules of appropriate shape spontaneously aggregate to form bilayers, creating small closed vesicles whose aqueous contents are isolated from the external medium (Figure 6-100). The phenomenon can be demonstrated in a test tube by simply mixing phospholipids and water together: under appropriate conditions, small vesicles will form. All present-day cells are surrounded by a plasma membraneconsisting of amphipathic molecules—mainly phospholipids—in this configuration; we discuss these molecules in detail in Chapter 10.
Figure 6-100

Formation of membrane by phospholipids. Because these molecules have hydrophilic heads and lipophilic tails, they align themselves at an oil/water interface with their heads in the water and their tails in the oil. In the water they associate to form
(more...)
Presumably, the first membrane-bounded cells were formed by the spontaneous assembly of a set of amphipathic molecules, enclosing a self-replicating mixture of RNA (or pre-RNA) and other molecules.
It is not clear at what point in the evolution of biological catalysts this first occurred. In any case, once
RNA molecules were sealed within a closed membrane, they could begin to evolve in earnest as carriers of genetic instructions: they could be selected not merely on the basis of their own structure, but also according to their effect on the other molecules in the same compartment. The nucleotide sequences of the RNA molecules could now be expressed in the character of a unitary living cell.
How Did Protein Synthesis Evolve?
The molecular processes underlying protein synthesis in present-day cells seem inextricably complex.
Although we understand most of them, they do not make conceptual sense in the way that DNA transcription, DNA repair, and DNA replication do. It is especially difficult to imagine how protein synthesis evolved because it is now performed by a complex interlocking system of protein and RNA molecules; obviously the proteins could not have existed until an early version of the translation apparatus was already in place. Although we can only speculate on the origins of protein synthesis and the genetic code, several experimental approaches have provided possible scenarios.
In vitro RNA selection experiments of the type summarized previously in Figure 6-97 have produced
RNA molecules that can bind tightly to amino acids. The nucleotide sequences of these RNAs often contain a disproportionately high frequency of codons for the amino acid that is recognized. For example, RNA molecules that bind selectively to arginine have a preponderance of Arg codons and those that bind tyrosine have a preponderance of Tyr codons. This correlation is not perfect for all the amino acids, and its interpretation is controversial, but it raises the possibility that a limited genetic code could have arisen from the direct association of amino acids with specific sequences of RNA, with
RNAs serving as a crude template to direct the non-random polymerization of a few different amino acids. In the RNA world described previously, any RNA that helped guide the synthesis of a useful polypeptide would have a great advantage in the evolutionary struggle for survival.
In present-day cells, tRNA adaptors are used to match amino acids to codons, and proteins catalyze tRNA aminoacylation. However, ribozymes created in the laboratory can perform specific tRNA aminoacylation reactions, so it is plausible that tRNA-like adaptors could have arisen in an RNA world.
This development would have made the matching of “mRNA” sequences to amino acids more efficient, and it perhaps allowed an increase in the number of amino acids that could be used in templated protein http://www.ncbi.nlm.nih.gov/books/NBK26876/ 6/8

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synthesis.
Finally, the efficiency of early forms of protein synthesis would be increased dramatically by the catalysis of peptide bond formation. This evolutionary development presents no conceptual problem since, as we have seen, this reaction is catalyzed by rRNA in present-day cells. One can envision a crude peptidyl transferase ribozyme, which, over time, grew larger and acquired the ability to position charged tRNAs accurately on RNA templates—leading eventually to the modern ribosome. Once protein synthesis evolved, the transition to a protein-dominated world could proceed, with proteins eventually taking over the majority of catalytic and structural tasks because of their greater versatility, with 20 rather than 4 different subunits.
All Present-day Cells Use DNA as Their Hereditary Material
The cells of the RNA world would presumably have been much less complex and less efficient in reproducing themselves than even the simplest present-day cells, since catalysis by RNA molecules is less efficient than that by proteins. They would have consisted of little more than a simple membrane enclosing a set of self-replicating molecules and a few other components required to provide the materials and energy for their replication. If the evolutionary speculations about RNA outlined above are correct, these early cells would also have differed fundamentally from the cells we know today in having their hereditary information stored in RNA rather than in DNA (Figure 6-101).
Figure 6-101

The hypothesis that RNA preceded DNA and proteins in evolution. In the earliest cells, pre-RNA molecules would have had combined genetic, structural, and catalytic functions and these functions would have gradually been replaced by RNA. In present-day (more...)

Evidence that RNA arose before DNA in evolution can be found in the chemical differences between them. Ribose, like glucose and other simple carbohydrates, can be formed from formaldehyde
(HCHO), a simple chemical which is readily produced in laboratory experiments that attempt to simulate conditions on the primitive Earth. The sugar deoxyribose is harder to make, and in present-day cells it is produced from ribose in a reaction catalyzed by a protein enzyme, suggesting that ribose predates deoxyribose in cells. Presumably, DNA appeared on the scene later, but then proved more suitable than RNA as a permanent repository of genetic information. In particular, the deoxyribose in its sugar-phosphate backbone makes chains of DNA chemically more stable than chains of RNA, so that much greater lengths of DNA can be maintained without breakage.
The other differences between RNA and DNA—the double-helical structure of DNA and the use of thymine rather than uracil—further enhance DNA stability by making the many unavoidable accidents that occur to the molecule much easier to repair, as discussed in detail in Chapter 5 (see pp. 269–272).
Summary
From our knowledge of present-day organisms and the molecules they contain, it seems likely that the http://www.ncbi.nlm.nih.gov/books/NBK26876/ 7/8

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The RNA World and the Origins of Life - Molecular Biology of the Cell - NCBI Bookshelf

development of the directly autocatalytic mechanisms fundamental to living systems began with the evolution of families of molecules that could catalyze their own replication. With time, a family of cooperating RNA catalysts probably developed the ability to direct synthesis of polypeptides. DNA is likely to have been a late addition: as the accumulation of additional protein catalysts allowed more efficient and complex cells to evolve, the DNA double helix replaced RNA as a more stable molecule for storing the increased amounts of genetic information required by such cells.
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