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Proteins perform all the chemical reactions needed to keep a cell alive; thus, it is essential to assemble them correctly. They are made by molecular machines called ribosomes, which follow a sequence of instructions written in genetic code in molecules known as mRNAs. Ribosomes essentially read the genetic code three letters at a time; each triplet either codes for the insertion of one of 20 building blocks into the emerging protein, or serves as a signal to stop the process. It is critical that, after reading one triplet, the ribosome moves precisely three letters to read the next triplet. If, for example, the ribosome shifted just two letters instead of three – a phenomenon known as “frameshifting” – it would completely change the building blocks that were used to make the protein. This could lead to atypical or aberrant proteins that either do not work or are even toxic to the cell.
For a variety of reasons, ribosomes will often stall before they have finished building a protein. When this happens, the ribosome is more likely to frameshift. Cells commonly respond to stalled ribosomes by recruiting other molecules that work as quality control systems, some of which can disassemble the ribosome and break down the mRNA. In budding yeast, one part of the ribosome – named Asc1 – plays a key role in recruiting these quality control systems and in mRNA breakdown. If this component is removed, stalled ribosomes frameshift more frequently and, as a result, aberrant proteins accumulate in the cell. Since the Asc1 recruiter protein sits on the outside of the ribosome, it seemed likely that it might act through other factors to stop the ribosome from frameshifting when it stalls. However, it was unknown if such factors exist, what they are, or how they might work.
Now, Wang et al. have identified two additional yeast proteins, named Mbf1 and Rps3, which cooperate to stop the ribosome from frameshifting after it stalls. Rps3, like Asc1, is a component of the ribosome, while Mbf1 is not. It appears that Rps3 likely stops frameshifting via an interaction with the incoming mRNA, because a region of Rps3 near the mRNA entry site to the ribosome is important for its activity. Further experiments then showed that the known Asc1-mediated breakdown of mRNAs did not depend on Mbf1 and Rps3, but also assists in stopping frameshifting. Thus, frameshifting of stalled ribosomes is prevented via two distinct ways: one that directly involves Mbf1 and Rps3 and one that is promoted by Asc1, which reduces the amounts of mRNAs on which ribosomes frameshift.
These newly identified factors may provide insights into the precisely controlled protein-production machinery in the cell and into roles of the quality control systems. An improved understanding of mechanisms that prevent frameshifting could eventually lead to better treatments for some human diseases that result when these processes go awry, which include certain neurological conditions.
