A few days ago I wrote about Ron Breaker and Riboswitches, and today I was alerted to this really neat advanced online publication by the Breaker group on how a riboswitch in Neurospera regulates alternative splicing. Wow.
So what is happening?
When the fungi Neurospora crassa is exposed to thiamine, it takes up this vitamin B1 precursor and phosphorylates it to form thiamine pyrophosphate (TPP). This small metabolite then binds to an RNA element found within an intron in the NMT1 pre-mRNA. These RNA folds that bind to small molecules are called aptamers and when these aptamers regulate how the mRNA is read by the ribosome they are called riboswitches. Well it turns out that this riboswitch does not directly regulate how the ribosome engages the NMT1 transcript but rather modifies how the NMT1 transcript is spliced as seen below.
So when cells are grown in the absence of thiamine ("-"), the NMT1 pre-mRNA ("i-1") is spliced into a small mature mRNA ("I-3"). In contrast when cells are grown in the presence of thiamne ("+") then I-1 is spliced into a larger transcript ("I-2"). This larger transcript is due to a shift in the 5' splice site (see diagram above) from the first "GU" site to the second "GU" site. As a result the longer transcript incorporates two upstream open reading frames (uORFs). When the ribosome engages this alternatively spliced transcript (I-2), it reads the upstream reading frames and falls off before it can translate the downstream open reading frame that encodes a key enzyme in the thiamine biosynthetic pathway.
Now not only is thiamine regulating the production of the NMT1 transcript through this riboswitch, but it is likely that it engages two other riboswitches that regulate the splicing of two other key transcripts.
Very cool stuff.
So do animals have riboswitches?
Ming T. Cheah, Andreas Wachter, Narasimhan Sudarsan & Ronald R. Breaker
Control of alternative RNA splicing and gene expression by eukaryotic riboswitches
Nature advance online publication 29 April 2007 | doi:10.1038/nature05769