What is all about ribosomes? Undoubtedly, readers will quickly make the connection between the title of this short essay and the recent awarding of the 2009 Nobel Prize in Chemistry to three whose work has centered on the ribosome. The Nobel prize announcement emphasized the links between ribosomes and antibiotics, rightly focusing attention on the fact that many antibiotics target the bacterial ribosome, different as it is from its eukaryotic (cytosolic) counterpart in important ways. What I want to do is to ramble on about some other aspects of ribosomes that I find fascinating. Hopefully, by turning some features of biology on their heads, readers will think differently about genomes, gene expression, and other facets of molecular biology.
First, lets move beyond the clinical applications, step back for a few moments, and look at the ribosome in the cell. With all due respect to plant scientists who hold up rubisco as the most abundant protein in nature, the ribosome is arguably the most abundant complex in nature. There may be as many as 10^7 ribosomes in the cytoplasm of a mammalian cell, each consisting of four RNAs and more than 80 proteins. The energy budget of a cell is similarly skewed towards the ribosome – I have read estimates placing the proportion of the cellular energy budget that goes to translation as being between 30%-75%. For comparison, transcription is usually estimated as consuming 5% of the energy of a cell, and DNA replication a much smaller fraction than even this. These are interesting numbers and should make one pause whenever statements to the effect that genome size may be selected for or against based on the appeals to energy efficiency. When it comes to the gene expression machinery, it is translation that most significantly impacts the energy budget of the cell.
In eukaryotes, three of the ribosomal RNAs (or rRNAs) are encoded in a single transcription unit. This unit is present in many copies, such that 200 or more copies of the rRNA transcription unit may exist in a typical genome. The fourth rRNA (so-called 5S rRNA) is also encoded by a highly-repeated gene family (again, many more than 200 members). Ribosome biogenesis is organized within its own cellular compartment (the nucleolus) and occupies the talents of more than 200 proteins (over and above the actual subunits of the ribosome itself). In terms of protein, this amounts to between 2 and 10% of the total genetic resources of a cell. In terms of gene expression, this range is higher. In terms of RNA, transcription of rRNA consumes a disproportionate amount of the efforts of the cell, such that two RNA-dependent RNA polymerases are dedicated to the production of ribosomal RNAs (I know, polIII also makes tRNAs, etc., but I’m invoking poetic license here).
The story in prokaryotes is equally impressive. Bacterial cells may possess as many as 100,000 ribosomes, with as much as 50% of the dry mass of a bacterial cell consisting of the prokaryotic ribosome (three RNAs and more than 50 proteins). Ribosomal protein synthesis may consume 30% of the cell’s translation energy budget, and rRNA transcription may acocunt for as much as 70% of all transcription that occurs in a bacterial cell. E. coli possesses seven rRNA transcription units (or operons); the ca. 30,000 bp of coding information amounts to about 1% (in round numbers) of the total bacterial genome. The 50+ ribosomal protein genes are almost 2% of the total number of bacterial genes. I haven’t an off-the-top of my head number for the numbers of proteins that are involved in bacterial ribosome assembly, but it should be clear that ribosomes are the single most prominent feature of the bacterial cell.
The point of these preceding paragraphs is to impress upon the reader that ribosomes are important. But it is also to lay a foundation for a somewhat unconventional way to look at a cell. Usually, and especially when thinking about genetics, gene expression, and the like, the emphasis is on DNA. Cellular reproduction is about DNA replication, heredity is about DNA transmission, gene expression is about the handling of DNA. But what if we place the ribosome at the center of the cell (as the preceding considerations would seem to demand)? For example, we might consider cellular reproduction as a matter of the reproduction and propagation of ribosomes. This changes the way we might view the process of heredity – DNA would amount to a storage form for ribosomal RNA, akin (in some senses) to the way that DNA is a storage form of a sort for retroviruses (1). Replication would amount to the process of rRNA transcription. In this context, organismal and population biology reduces to a matter of the ways by which ribosomal RNAs can propagate and compete in the biosphere, and natural selection (when it is in operation) becomes at its core a matter of the effects of variability on the functioning of the ribosome. Etc., etc., etc….
This may sound like an interesting but pretty arcane exercise, to turn so much of biology on its head like this. But this perspective has much applicability to the origin and early evolution of life. I think that, for the most part, it is accepted that the so-called RNA World was a precursor to the world of life as we know it. However, most of the interest in the RNA World seems (to me, at least) to revolve around the origins and nature of the first replicating RNA genome. One theme of sorts is that, whatever the first RNA genome, it was eventually supplanted by DNA and is probably lost irretrievably to the darkness of the very distant past. The above considerations permit a somewhat different (NOT exclusive of other views, just something I don’t see often mentioned) perspective to be developed. Conveniently, this perspective allows me to mention one controversy that accompanies the 2009 Nobel Prize in Chemistry.
One possible “slight” in this years award is the fact that Harry Noller was not among the prize recipients. I don’t intend to speculate about the internal machinations, rumors, politics, are like subjects, but raise Noller’s name because he was the pioneer who championed the idea and established the fact that the ribosome is a ribozyme; peptide bond formation is catalyzed by rRNA and not protein. In light of the above, it follows that the most important and central feature of living things is a catalytic RNA. I would argue that the origins of this catalytic RNA lie at the heart of the origins of life. Whatever and however RNA was produced at the dawn of (prebiotic) life, the first threshold to be crossed involved the origination of the peptidyl transferase core of the rRNA. As Peter Moore suggested (in so many words) in his chapter of The RNA World, the origin of life is a matter of the origin of the ribosome. And, as I hint at above and in the footnote, the evolution of life as we know it may in some ways be viewed as the evolution of, not a DNA World, but a Retro World. What follows from this is the realization is that, far from being lost in the deep past, the first RNA genome is actually very much alive today; it is ribosomal RNA.
(1). The parallels with viruses are much more numerous, but for now I will not explore this theme, EXCEPT to explicitly state that we can correctly consider life as we know it to be “retro” – an RNA genome (ribosomal RNA) that replicates through an elaborate DNA intermediate. Perhaps some readers might get interested in this, either here or in their real lives.