Transcription and Translation

No-go Decay

A major field of research in the “RNA field” is the quality control of mRNA production.

Remember from the central dogma:
DNA=>RNA=>Protein

When “genes are activated”, what is really going on is that a DNA segment (i.e. the gene) is copied into RNA, that is then processed to form messenger RNA (mRNA) in the nucleus. During this processing, RNA acquires several modifications: a Cap is added to the front end (5′ end), a poly-A tail is added to the back end (3′ end), and any non-coding regions are spliced out of the middle. The mRNA is then exported from the nucleus into the cytoplasm where it can be translated into protein by the mighty ribosome.

But what happens if the mRNA is misprocessed? Or what happens if a gene acquires a mutation resulting in aberrant mRNAs?

The eukaryotic cell has various mechanisms to deal with any bad mRNA.

If an RNA looses its cap, 5′ exonucleases rapidly chew up the capless-RNA.
If an RNA looses its tail, the exosome, a huge complex will crunch the RNA up.
If a stop codon is introduced in the middle of a gene by mutation, the RNA is degraded by the nonsense-mediated decay machinery. It’s a complicated (but fascinating) story that involves splicing and the exon-junction complex, maybe I’ll write something up on this some other time.
If there is no stop codon in the gene (lost by an unfortunate mutation) the RNA is destroyed by the non-stop decay machinery.
i-1b3943770b00b3905fa1b1b3e6c096e8-nogorna.jpg

As you can tell the cell takes great care in monitoring the quality of its mRNA.

So what happens when RNA accumulates a mutation that hampers the ribosome’s ability to translate it? For example if a large stem loop of other RNA fold impeded the ribosome’s path along the mRNA. Well it had been previously noted that such RNAs are also targeted for destruction, but the underlying mechanism was unknown. In the March 23rd issue of Nature, Meenakshi Doma from Roy Parker’s uses yeast to tease out genes that may be involved in this new RNA-quality-control process that they call No-go decay.

They show that this type of mRNA is snipped into two, right at the stemloop and that the nucleases are recruited there by the stalled ribosome. What is the nuclease? The identity of this nuclease is unknown, however Doma and Parker provide evidence that one protein, Dom34p is required, while another protein Hbs1p may also play a role in generating the RNA fragments. These two proteins share sequence similarity with factors that release the ribosome after the translation of protein is complete, suggesting that a similar mechanism may help unhook stalled ribosomes from bad mRNA.

My one complaint about this paper is that Doma and Parker did not show that nogo-decay itself is impaired in yeast strains lacking the dom34, or hbs1 genes. (i.e. Are these mRNAs stabilized in dom34 or hbs1 knockouts?) They claim that Ski7p, another protein involved in different RNA decay pathways may also play a role in nogo-decay, however stemloop containing mRNAs are not stable in ski7 knockouts. But besides this point, this is a very nice story.

Ref: Meenakshi K. Doma and Roy Parker. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature (2006) 440:561-564.