Cut yourself
What came first? The DNA or the protein? Evolutionary biologists are looking for the answer in the middle: RNA molecules with catalytic properties - called ribozymes - could have been at the beginning of life. New details of these biochemical hermaphrodites are now revealed.
All biocatalysts are proteins. All? No! A group of small molecules continues to resist this biochemical dogma. Until the 1980s, molecular biologists were firmly convinced that protein enzymes are the only molecules in life that can accelerate biochemical reactions, i.e. have a catalytic effect.
But this gave rise to an evolutionary biological problem: the building instructions for enzymes, like those of all proteins in an organism, are encoded in the DNA. However, the genetic material in turn needs enzymes in order to spread the protein message and itself. What then came first in the primordial soup of life? DNA or Protein?
In 1981, the American biochemist Robert Cech presented a solution to this classic chicken-and-egg problem. In the ciliate Tetrahymena pyriformis, he found ribonucleic acids that can cut themselves – i.e. without the involvement of proteins. Two years later, his Canadian colleague Sidney Altman discovered enzymes that consist of a protein and an RNA part. However, it was not the protein component that had a catalytic effect, but – the RNA. These RNA enzymes, ribozymes for short, disproved biochemical dogma and brought the two discoverers the Nobel Prize in Chemistry in 1989.
Now everything seemed so simple: neither the hen (read: DNA) nor the egg (protein) was at the beginning, but the mediator between the two. The small molecules that reproduced themselves without outside help and then at some point produced the first proteins wafted around in an "RNA world".
Ribozymes were of course not satisfied with the role of a midwife of life, but still fulfill valuable services today. Of particular interest are the self-cutting RNA threads, which, strictly speaking, violate the chemical definition of a catalyst - since they emerge modified from the reaction - but are located in important metabolic pathways. One of these "riboswitches" goes by the abbreviation glmS and controls the enzyme glucosamine-6-phosphate synthase required for the construction of the cell wall in bacteria.
Daniel Klein and Adrian Ferré-D'Amaré explained how he does it [1]. The two scientists from the Fred Hutchinson Cancer Research Center in Seattle crystallized three states of the glmS ribozyme from the bacterium Thermoanaerobacter tengcongensis. This allowed them to elucidate the structure of the ribozyme before and after cleavage, as well as the intermediate stage with a bound glucosamine-6-phosphate analogue.
How does the switch work? The ribozyme contains the mRNA strand that codes for glucosamine-6-phosphate synthase. This enzyme produces the sugar glucosamine-6-phosphate, which the bacterium uses to build its cell wall. If there is an excess of the building block, it binds to the ribozyme, which then chops itself up along with the attached mRNA. This means that no new enzyme can be produced - glucosamine-6-phosphate thus inhibits its own production via the riboswitch.
While such riboswitches appear to be commonplace in bacteria, science knows few of them in higher organisms, including humans. In the course of our evolution, have we dispensed with the little helpers we may have inherited from the RNA world?
The researchers led by Jack Szostak from the Massachusetts General Hospital in Boston have now systematically searched the human genome for ribozymes [2]. To do this, they prepared a DNA library with circular snippets only about 150 base pairs long, produced RNA strands from them and tested them for their self-cutting skills.
The researchers were able to track down a total of four of these self-crushers. One of them is in the first intron of the CPEB3 gene, i.e. in a section of the hereditary factor that is excised again after it has been read. Surprisingly, the snippet hidden here resembles a ribozyme of the hepatitis delta virus (HDV).
It was further shown that the ribozyme was located within this gene in all mammals, including marsupials, but not in other vertebrates. According to this, it should have formed sometime between 200 and 130 million years ago, when the last common ancestors of marsupials and higher mammals walked the earth. Since then it has practically not changed, so it must fulfill an important function.
Which remains a mystery. The protein produced by the gene CPEB3 (cytoplasmic polyadenylation element- b inding protein 3) regulates gene reading in various tissues, such as heart, skeletal muscle and brain, and may be involved in learning. The researchers do not yet know whether the ribozyme acts as a switch here.
Perhaps more exciting is the fact that HDV only affects humans. The researchers therefore assume that the ribozyme is not a viral inheritance, but vice versa: the virus caught it from humans. This ribozyme would therefore not be a holdover from the time of the RNA world, but a newly created achievement of mammals.
