Me – strange? Nonsense! NONSENSE MEDIATED DECAY provides a way to get rid of early stop-signed mRNA! And I hope yoUAGree it’s immature to start lAUGhing at PREMATURE STOP CODONS!

Proteins are like molecular workers, and they’re made by other workers, protein/RNA complexes called RIBOSOMES. The instructions for proteins are written in DNA form in GENES -> a messenger RNA (mRNA) copy of these instructions is then made and this copy serves as “road” that the ribosome travels along, “reading” the RNA’s 3-nucleotide (RNA letter) “words” called CODONS, and inserting the amino acid (protein letter) that word spells.

As I’m sure pavers will tell you, roads don’t make themselves! And, as I’m sure drivers will tell you, not all roads are safe to travel on! Your cells need a “transit authority” to provide quality control and make sure that the road is safe for the mRNA to travel on. Because problems can arise if it sees a stop sign before you’re actually at the end – a PREMATURE TERMINATION CODON (PTC). Stopping there gives you a partial protei . And those partial proteins can cause full-on problems.

If you could detect that partial protein, you could tag it with ubiquitin, and send it to the protein shredder (proteasome). more on this here: https://bit.ly/ubiquitinylation

And you do do that. But that’s not enough. You also want to get rid of the defective road or else ribosomes will just keep on making the partial proteins. So you also need to get rid of the mRNA. And you can do this through NONSENSE-MEDIATED mRNA DECAY (NMD)

The mRNA road-laying begins with TRANSCRIPTION, where a molecule called RNA POLYMERASE (RNA Pol) makes an RNA copy of the gene. But this copy’s word-for-word, including “margin notes” called INTRONS that INTerrupt the parts that get EXpressed (turned into proteins) – EXONS. So before the mRNA leaves the DNA’s “home” (a membrane-bound compartment called the NUCLEUS) it gets edited in a process called SPLICING, where the introns get removed and the exons stitched together. more here: https://bit.ly/altsplicing

This is carried out by a complex called the SPLICEOSOME and it “leaves behind workers” in the form of EXON JUNCTION COMPLEXES (EJCs) – a group of proteins left ~20-24 letters upstream of the place where exons were joined.

These EJCs go with the mRNA as it’s exported out of the nucleus and into the mRNA’s “turf” – the general cellular interior called the CYTOPLASM, where the ribosomes are. And the EJCs even pick up new friends. These guys didn’t do any of that splicing work but they see the workers hanging out there and decide it looks like fun (maybe there’s free Gatorade…) Anyways, the workers get the message that their shift’s over in a kinda harsh way – the ribosome basically just pushes them off the road as it travels through the 1st time (the so-called “pioneer round” of translation).

The ribosome plows through all the workers until it reaches the word for “Stop” (termination codon) and then release factors come and release the growing peptide. If it reaches the true end of the road (at least the protein-coding part) all those workers will be gone. But if it stops too early, the workers past the Premature Termination Codon (PTC) won’t have gotten the message and they’ll still be there.

And some of the friends they bring in are “tricksters” – they like to play practical jokes on the ribosome – instead of letting the ribosome push them, they push the ribosome and remodel its road.

Usually, the ribosome doesn’t have to worry about them because it recruits friends of its own. In addition to getting spliced, precursor-mRNA (pre-mRNA) gets “capped” and “tailed” – extra RNA letters are added on to all pre-mRNAs and thus serve as a sort of sign saying hey ribosomes, there’s a road here. And the cap and tail are recognized by various cap and tail binding proteins. And some of these help promote proper termination.

But when you have a PTC, the helpers are too far away to help the ribosome out, so NMD happens instead. Termination factors are called in as usual (since there is a stop codon there, forming a so-called “SURF” complex (SMG1, UPF1, eRF1 & eRF3) that’s associated with the terminating ribosome. but instead of interacting with the proteins on the tail, SURF interacts with the proteins at the EJC and this forms a “DECID” complex that gets to work.

The key player is an RNA helicase called UPF1. It changes the mRNA’s shape, making it harder for stuff to stay on. And its friends egg it on (in ways like binding it or phosphorylating it (adding a negatively-charged phosphate group) in a way that causes it to adopt a more active shape.

There are a lot of friends involved because you have to take care of the mRNA, the partial protein, and the ribosome. one of the friends it calls in is a pair of “RNA scissors” (an endonuclease) called SMG6 which cuts the mRNA. This exposes naked ends which get chewed up by RNA end-chewers (exonucleases).

You also want to get rid of the partial protein, so ubiquitin ligases tag it with a chain of the small protein ubiquitin. The release factors help kick it out of the ribosome, and it gets sent the proteasome to get shredded.

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The ribosome’s still useful though, and UPF1 and the release factors help take it apart and recycle it.

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Early stop signs aren’t the only problems the mRNA road can have – if there’s a really steep hill (strong secondary structure like a hairpin in the mRNA) the ribosome can stall. Or it can stall at “rare codons” because cells don’t stock up on the corresponding transfer RNAs (tRNAs) needed to bring them the corresponding amino acid. In those cases, you have a process called NO-GO DECAY (NGD). You can learn more about it here: http://bit.ly/2GACRzp

It’s really similar except that it calls in different helpers. Since there isn’t a stop codon it has to call in special release factors and a different endonuclease (inside cutter) but then it can use the same exonucleases and stuff.

But why would you have a premature stop codon anyway? Why have our cells evolved to have such an intricate mechanism for dealing with them? There aren’t any spaces in between codons, so where you start reading matters -> thismakessense but th ismakessense doesn’t. because the words are 3-letters-long, there are 3 different “reading frames: I can start reading at the T, or the K & be in the same reading frame: THIsmaKESsenSE is in the same frame as thismaKESsenSE. But, if I start from the H or the I, I’ll have shifted frames: tHISmakESSensE or thISMakeSSEnse. You still read all the letters but you read them a sdi ffe ren two rds.

Thankfully the ribosome knows where to start reading because it looks for the word for start, AUG. Then it stays in the frame it starts at and goes until it reads stop. Then, instead of adding an amino acid, it releases the chain.

There are 4 letters in the RNA alphabet (A, U, G & C), so 64 possible codons. 3 of these spell “stop”: UAG, UAA, & UGA

A stop codon can be “hidden” – yoUGAin a stop codon if you read it a certain way. So if there’s a mistake with the transcription (DNA->RNA copying) or splicing (removing the introns) you can gainn or lse letters which can make a stop sign appear where there shouldn’t be one. Or yoUGAn have an incorrect letzer put it which can create a PTC. We call these stop-codon-generating mutations NONSENSE MUTATIONS. So, NMD provides a way for your cells to detect “bad” mRNA that sneaks past the spliceosomal editors!

In addition to its quality control role, there’s growing evidence that NMD can play a role in getting rid of unwanted but not prematurely-terminated mRNA and it’s an exciting field to watch!

And watch people are because NMD is implicated in lots of diseases. Mutations in mRNA that are caused by transcription or splicing errors aren’t that bad because it’s just that one copy and you still have the permanent DNA version. But diseases can occur when there’s a PTC-causing mutation in that DNA version. Then all the mRNA made from it will be affected. So scientists are working on ways to get cells to ignore the PTC.

more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0

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