eTopics

eTopic 17.1 The RNA World: Clues for Modern Medicine

How did the cells of the hypothetical RNA world evolve to use proteins? Tom Cech, Sidney Altman, and colleagues propose that the earliest RNA components of cells acquired peptide components to enhance stability, decreasing the tendency of RNA to hydrolyze (Fig. 1). As the peptide components increased through natural selection, the RNA component may have shrunk by reductive evolution (the loss of a trait in the absence of selection pressure) until all that remained were one or two nucleotides. Dinucleotide cofactors such as NADH persist in enzymes today, perhaps representing vestigial remnants of the RNA world.

Furthermore, the persistence of ribonucleotides in molecular mechanisms of gene regulation argues for an early central role of RNA in cell function. Bacterial operons for ribosomal components and for purine and pyrimidine biosynthesis are regulated not by DNA-binding proteins but by RNA molecules known as riboswitches, which interact with the DNA promoters (discussed in eTopic 15.2). Finally, many viruses have RNA genomes and ribozymes that interact with host cells in unique ways, as discussed in Chapters 6 and 11.

If cells acquired proteins through evolution, how did they acquire DNA? A controversial proposal by Patrick Forterre, at the Universit√© Paris-Sud in Orsay, France, is that DNA was acquired through viruses. As discussed in Chapters 6 and 11, many kinds of viruses are capable of inserting their genomes into a host cell for replication along with host chromosomes. Viruses could have evolved DNA as a modified form of chromosome that avoided cleavage by protective enzymes of the RNA-genomic host. A viral DNA molecule within a host cell could eventually acquire genes from the host RNA chromosome by recombination or reverse transcription. Host genes converted to DNA would tend to outlast their RNA counterparts because of DNA’s greater stability. Eventually, according to Forterre’s model, the entire host cell genome would be converted to DNA.

The study of life’s origin some billions of years ago may seem distant from modern human concerns. Yet investigation of early-life phenomena such as ribozymes has led to important developments in medical research. Jennifer Doudna and colleagues discovered the function of an unusual RNA component of hepatitis C virus (Fig. 2). The hepatitis viral mRNA possesses a specialized stem loop structure called an internal ribosome entry site (IRES). The IRES binds to a host ribosome and shuts down host protein synthesis while facilitating translation of the viral mRNA. The IRES then catalyzes cleavage of the RNA to complete the formation of viral genomes by rolling-circle replication.

Doudna published the first structure of an IRES bound to a ribosome initiation site (Fig. 2B). The IRES binds specifically to the ribosome at the mRNA recognition groove, so as to facilitate transcription of viral templates while excluding those of the host. Its tertiary structure positions a cytosine just right for catalyzing hydrolysis of the RNA backbone (Fig. 2C).

The study of viral ribosomes has led to the design of artificial ribozymes for chemotherapy. One goal is to design a ribozyme to cleave a gene transcript essential in cancer cells. The potential applications of artificial ribozymes have led to the start-up of several ribozyme companies; for example, Ribozyme Pharmaceuticals, Inc. (RPI) conducts clinical trials on ribozymes to treat cancer.

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Figure 1  Transition from the RNA world to modern cells. A. Nobel laureate Tom Cech (left) proposed a model for the RNA world transition to protein-based cells. He is shown here discussing a student’s poster at an international workshop on ribozymes in Dundee, Scotland, 2001. B. Earliest cells may have been composed of RNA enzymes (ribozymes). As the RNA cells evolved, the ribozymes acquired protein subunits that eventually assumed most of the catalytic functions. Remnants of the original RNA may persist as nucleotide cofactors such as NADH. C. Nobel laureate Sidney Altman (right) studies a genomic sequence with a student at Yale University. Source: Part B from Yale Bull. 2002–03 Vol. 2 , No. 1. David Lilley, University of Dundee, UK ¬© 2001 Yale University.

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Figure 2  A viral ribozyme.  A. Jennifer Doudna elucidates the structure and function of ribozymal components of viruses such as hepatitis C virus. B. The internal ribosome entry site (IRES) of the hepatitis C viral mRNA, showing the catalytic site. (PDB code: 1VC5) C. The IRES is folded such that a specific cytosine is positioned to catalyze hydrolysis of the RNA backbone. Source: Part B from J. Doudna and T. Cech. 2002. Nature 418:222.

Courtesy of Ronald Sutherland, UC, Berkeley.