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FIGURE 20.05 Assembly and Duplication of Random RNA

A mixture of nucleosides and polyphosphates can form random stretches of RNA in the presence of zinc ions. The first strand of RNA forms very slowly. However, once the first strand is assembled, it may be used as a template to assemble complementary strands of RNA. Such template driven assembly of nucleotides is much faster than formation of the original random RNA strand. However, the non-enzymatic synthesis of RNA incorporates many wrongly paired bases.

RNA molecules with enzyme activity include ribosomal RNA, ribonuclease P, self-splicing introns and viroids.

that the primitive nucleic acid replicated alone and a protective protein coat was added later.

One rather extreme viewpoint is the idea that the earliest organisms had both genes and enzymes made of RNA and formed a so-called "RNA world." This idea was proposed by Walter Gilbert in 1986 and seeks to avoid the paradoxical problem that nucleic acids are needed to encode proteins, but that enzymes made of protein are needed to replicate nucleic acids. During the RNA world stage, RNA supposedly carried out both functions. Later, proteins infiltrated and took over the role of enzymes and DNA appeared to store the genetic information, leaving RNA as a mere intermediate between genes and enzymes.

Several examples illustrate the ability of RNA to perform enzymatic reactions as well as encode genetic information. These cases favor the primacy of RNA:

1. Ribozymes are single-use RNA molecules that are enzymatically active. A genuine enzyme processes large numbers of other molecules, and does not become altered during the reaction. Therefore, self-splicing RNA is not a true enzyme because it works only once. There is a growing list of known and suspected ribozymes. The most important is the ribosomal RNA of the large subunit, which is directly involved in the reactions of protein synthesis (see Ch. 8). One of the best-known ribozymes is ribonuclease P. This enzyme has both RNA and protein components and processes certain transfer RNA molecules. It is the RNA part of ribonuclease P that carries out the reaction. The protein serves only to hold together the ribozyme and the transfer RNA it operates on. In concentrated solution, the protein is not even necessary, and the RNA component will work on its own.

2. Self-splicing introns ("group I" introns) are an example of catalytic RNA. The genes of eukaryotic cells are often interrupted by non-coding regions (the introns), which must be removed from the messenger RNA before translation into protein. Normally, this is done by a spliceosome made up of several pro-

ribonuclease P A ribozyme found in many bacteria that processes certain transfer RNA molecules ribozyme RNA molecule that is enzymatically active

RNA world The hypothetical stage of early life in which RNA encoded genetic information and carried out enzyme reactions without the need for either DNA or protein

Newly made nucleic acid molecules all start with a stretch of RNA.

Artificial ribozymes can be isolated by screening pools of random RNA sequences for particular enzymatic reactions.

teins and small RNA molecules. Occasionally, the intron RNA splices itself out without help from any protein. Such self-splicing is found in a few nuclear genes of some protozoans, in the mitochondria of fungal cells, and the chloroplasts of plant cells (see Ch. 12 for details).

3. Viroids are infectious RNA molecules that infect plants. As noted in Chapter 17, viroid RNA carries out a self-cleavage reaction during replication, i.e. viroids act as ribozymes.

4. DNA polymerase cannot initiate new strands but can only elongate pre-existing strands (see Ch. 5). Primers made of RNA must be used whenever new strands of DNA are started. RNA polymerase is capable both of initiation and elongation. This suggests that RNA polymerase may have evolved before DNA polymerase.

5. Small guide molecules of RNA are used in a variety of processes. These include the removal of introns, the modification and editing of messenger RNA (see Ch. 12 for details) and the extension of the ends of eukaryotic chromosomes by telomerase.

6. Riboswitches are recently discovered binding motifs in RNA that directly bind small molecules and so control gene expression in the absence of regulatory proteins (see Ch. 11 for details).

In a way, the critical question is whether RNA can copy itself without the involvement of DNA or help from protein enzymes. Although no RNA polymerases that are ribozymes still exist, it has proven possible to generate them artificially. Altered RNA molecules can be selected by a form of Darwinian evolution at the molecular level. Pre-existing ribozymes can be used as starting materials. Alternately, some experimenters have used random pools of artificially generated RNA sequences. In one experiment, RNA molecules showing primitive RNA ligase activity were selected from a pool of random RNA sequences. Such artificial ribozymes can link together two chains of RNA by a typical ligase reaction just like protein enzymes in modern cells. The best of these RNA ligase ribozymes was then subjected to further rounds of mutation and selection. The result was a ribozyme of 189 bases that uses an RNA template to synthesize a complementary strand of RNA with about 96-99% accuracy. This ribozyme adds single nucleotides, one at a time, to an RNA primer using nucleoside triphosphates as substrates (Fig. 20.06). However, it is very slow and can only extend chains by around 14 nucleotides because it is not "processive". In other words, the ribozyme dissociates from the template after adding each nucleotide, whereas true polymerases remain attached and proceed along the template adding nucleotides in quick succession.

One problem with the "RNA world" concept is that RNA is more reactive than DNA. Although RNA would form more easily than DNA under primeval conditions, it would also be less stable. Thus DNA, though slower to form initially, might tend to accumulate under such conditions. Moreover, the primeval soup would contain a mixture of the sub-components of both types of nucleic acid as well as proteins, lipids and carbohydrates. So it seems perhaps more likely that an ill-defined mixture, perhaps even hybrid nucleic acid molecules with both RNA and DNA components, emerged first.

The first cells probably used RNA in multiple roles some of which were later taken over by proteins or DNA.

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