Chapter 26 RNA METABOLISM
Expression of the information in a gene generally involves production of an RNA molecule transcribed from a DNA template. Strands of RNA and DNA may seem similar at first glance, differing only in that RNA has a hydroxyl group at the position of the aldopentose, and uracil usually replaces thymine. However, unlike DNA, most RNAs carry out their functions as single strands, strands that fold back on themselves and have the potential for much greater structural diversity than DNA (Chapter 8). RNA is thus suited to a variety of cellular functions.
RNA is the only macromolecule known to have a role both in the storage and transmission of information and in catalysis, which has led to much speculation about its possible role as an essential chemical intermediate in the development of life on this planet. The discovery of catalytic RNAs, or ribozymes, has changed the very definition of an enzyme, extending it beyond the domain of proteins. Proteins nevertheless remain essential to RNA and its cellular functions. In the biosphere of today, all nucleic acids, including RNAs, are complexed with proteins. In the case of RNA, these complexes are called ribonucleoproteins or RNPs. Some of these RNPs are quite elaborate, and RNA can assume both structural and catalytic roles within complicated biochemical machines.
All RNA molecules except the RNA genomes of certain viruses are derived from information permanently stored in DNA. During transcription, an enzyme system converts the genetic information in a segment of double-stranded DNA into an RNA strand with a base sequence complementary to one of the DNA strands. Four major kinds of RNA are produced. Messenger RNAs (mRNAs) encode the amino acid sequence of one or more polypeptides specified by a gene or set of genes. Transfer RNAs (tRNAs) read the information encoded in the mRNA and transfer the appropriate amino acid to a growing polypeptide chain during protein synthesis. Ribosomal RNAs (rRNAs) are constituents of ribosomes, the intricate cellular machines that synthesize proteins. Noncoding RNAs (ncRNAs) have a variety of catalytic, structural, and regulatory functions.
During replication the entire chromosome is usually copied, but transcription is more selective. Only particular genes or groups of genes are transcribed at any one time, and some portions of the DNA genome are never transcribed. The cell restricts the expression of genetic information to the formation of gene products needed at any particular moment. The sum of all the RNA molecules produced in a cell under a given set of conditions is called the cellular transcriptome. Given the relatively small fraction of the human genome devoted to protein-coding genes (about 2%), we might expect that only a small part of the human genome is transcribed. This is not the case. Transcriptome analyses have revealed that approximately 76% of the human genome is transcribed into RNA. The products are predominantly not mRNAs but rather ncRNAs. Many ncRNAs are involved in regulating gene expression by interaction with other RNAs, genomic DNA, or proteins. However, the rapid pace of their discovery has forced us to realize that we do not yet know the function of the majority of our genomic ncRNA transcripts.
In this chapter we examine the synthesis of RNA on a DNA template and the postsynthetic processing, location, and turnover of RNA molecules. In doing so, we encounter many of the specialized functions of RNA, including catalytic functions. We also describe systems in which RNA is the template and DNA the product, rather than vice versa. The information pathways thus come full circle and reveal that template-dependent nucleic acid synthesis has standard rules, regardless of the nature of template or product (RNA or DNA). This examination of the biological interconversion of DNA and RNA as information carriers leads inevitably to a discussion of the evolutionary origin of biological information and processing. We will be guided by four principles.
RNA is synthesized by RNA polymerases using DNA templates and ribonucleoside -triphosphates. RNA is made in the direction and complementary to the template DNA strand. Transcription is highly regulated and initiates by recruitment of the transcription machinery to gene promoters. Although bacterial and eukaryotic polymerases share many conserved features, the transcriptional machinery and its regulation are much more complex in eukaryotes.
Many RNAs must be modified and processed to become functional. RNAs can be modified by nucleases, by excision of certain RNA segments, and/or by chemical modification of the RNA nucleotides. In humans, nearly all mRNAs are capped, spliced, and polyadenylated before being exported from the nucleus for translation in the cytoplasm.
RNA can be used as a template for synthesis of DNA by reverse transcriptases. RNA carries genetic information that can be reverse transcribed into DNA. Retroviruses, such as HIV or those responsible for some cancers, must convert their RNA genomes into DNA by reverse transcription. Reverse transcription by telomerase is also responsible for producing the telomeres that protect the DNA found at the ends of eukaryotic chromosomes.
RNA can act as both a catalyst and carrier of genetic information. Ribozymes can catalyze chemical transformations using many of the same strategies as protein-based enzymes. The dual capacity of RNA as both a carrier of genetic information and a catalyst is support for the RNA world hypothesis for the evolution of life on Earth.
RNA is synthesized by RNA polymerases using DNA templates and ribonucleoside -triphosphates. RNA is made in the direction and complementary to the template DNA strand. Transcription is highly regulated and initiates by recruitment of the transcription machinery to gene promoters. Although bacterial and eukaryotic polymerases share many conserved features, the transcriptional machinery and its regulation are much more complex in eukaryotes.
Many RNAs must be modified and processed to become functional. RNAs can be modified by nucleases, by excision of certain RNA segments, and/or by chemical modification of the RNA nucleotides. In humans, nearly all mRNAs are capped, spliced, and polyadenylated before being exported from the nucleus for translation in the cytoplasm.
RNA can be used as a template for synthesis of DNA by reverse transcriptases. RNA carries genetic information that can be reverse transcribed into DNA. Retroviruses, such as HIV or those responsible for some cancers, must convert their RNA genomes into DNA by reverse transcription. Reverse transcription by telomerase is also responsible for producing the telomeres that protect the DNA found at the ends of eukaryotic chromosomes.
RNA can act as both a catalyst and carrier of genetic information. Ribozymes can catalyze chemical transformations using many of the same strategies as protein-based enzymes. The dual capacity of RNA as both a carrier of genetic information and a catalyst is support for the RNA world hypothesis for the evolution of life on Earth.