Open any introductory biology textbook and one of the first things learnt is that DNA spells out the instructions for making proteins, tiny machines that do much of the work in the body’s cells. Results from a study published in the journal Science defy textbook science, showing for the first time that the building blocks of a protein, called amino acids, can be assembled without blueprints, DNA and an intermediate template called messenger RNA (mRNA). A team of researchers from the University of Utah have observed a case in which another protein specifies which amino acids are added.
To put the new finding into perspective, it might help to think of the cell as a well-run factory. Ribosomes are machines on a protein assembly line, linking together amino acids in an order specified by the genetic code. When something goes wrong, the ribosome can stall, and a quality control crew is summoned to the site. To clean up the mess, the ribosome is disassembled, the blueprint is discarded, and the partly made protein is recycled.
The current study revealed a surprising role for one member of the quality control team, a protein conserved from yeast to man named Rqc2. Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of a total of 20), alanine and threonine, over and over, and in any order. Think of an auto assembly line that keeps going despite having lost its instructions. It picks up what it can and slaps it on, horn-wheel-wheel-horn-wheel-wheel-wheel-wheel-horn.
In this case, the teams state the protein is playing a role normally filled by mRNA.
Like a half-made car with extra horns and wheels tacked to one end, a truncated protein with an apparently random sequence of alanines and threonines looks strange, and probably doesn’t work normally. But the nonsensical sequence likely serves specific purposes. The code could signal that the partial protein must be destroyed, or it could be part of a test to see whether the ribosome is working properly. Evidence suggests that either or both of these processes could be faulty in neurodegenerative diseases such as Alzheimer’s, Amyotrophic lateral sclerosis (ALS), or Huntington’s.
The scientists first fine-tuned a technique called cryo-electron microscopy to flash freeze, and then visualize, the quality control machinery in action. The team actually caught Rqc2 in the act. But the idea was so far-fetched. The onus was on the researchers to prove it.
It took extensive biochemical analysis to validate their hypothesis. New RNA sequencing techniques showed that the Rqc2/ribosome complex had the potential to add amino acids to stalled proteins because it also bound tRNAs, structures that bring amino acids to the protein assembly line. The specific tRNAs they saw only carry the amino acids alanine and threonine. The clincher came when they determined that the stalled proteins had extensive chains of alanines and threonines added to them.
The team state they now plan to determine when and where this process happens, and what happens when it fails.