Friday, November 24, 2006

I'd be fired if that were my job   posted by amnestic @ 11/24/2006 06:04:00 PM

I've been trying to come up with some clever way of framing the latest RNAi work in a mythological context, but I'm afraid it isn't lending itself all that well. You see, the family of final effector proteins for RNA-induced silencing are called Argonautes. Why did they name them Argonautes and then fall off on their Apollonisian naming scheme? Beats me, but they are really going haywire now. They named one of the argonaute proteins Caesar!

In this report from Yigit et al., they knocked out every Argonaute family member in C. elegans, the lovely translucent worm genetic model system. You'd think there would be a tie-in there. The preview about the report is titled "Knocking out the Argonautes," but alas, the only knocking out I can discover involves Circe and the Odyssey cats. The worm has a rather different system for RNAi than we do. The focus of this paper was a whole class of Argonautes that worms have that there isn't a human or even drosophila homologue for. They are called SAGOs (say-go) for Synthetic secondary-siRNA ArGOnautes.

One of the purposes of RNAi is to defend against viral infection by using chopped up viral genomes as templates for small RNAs to load into RNA chomping or sequestering machines. In worms, this system is referred to as the exo-RNAi system. In the model proposed by Yigit et al., Worms differ from many other organisms in that they carry out their defensive mission in two steps. In step one, a primary the viral dsRNA is chopped up to produce template a fewsmall RNAs from both strands. These are loaded into a Primary Argonaute-containing silencing complex. When this complex chops up its targets it also happens to trigger an production of new small RNAs based off of the sequence upstream of its target sequence in the viral RNA. These are the secondary siRNAs. In step 2, a Secondary Argonaute (SAGO) complex is loaded with these secondary siRNAs. The SAGOs don't have the ability to cleave RNAs. They can only bind them and perhaps drag them to some RNA degradation center or other.

Things I learned from this paper and the associated preview include: You can predict whether an Argonaute protein will have RNA cleavage activity based on the conservation of three amino acid residues (two aspartic acids and a hisitidine); in an uncommon twist, humans actually have less of a protein class than other organisms, 8 AGOs as opposed to 27 in worms and 10 in mustard plants (flies have 5, so we are still superior to flies), ~50 in the Argonautika; multiple RNAi (endo- and exo-) pathways feed into the second (SAGO) step in the worm such that the availability of SAGOs can be a limiting factor, and increasing or decreasing the activity of one of the competing pathways can affect the efficiency of the other; worms have an endo-RNAi pathway that is somehow distinguishable from their miRNA pathway, though I'm not sure what the distinction is just yet. My understanding was that I could call endogenously produced small interfering RNAs microRNAs. From their model, it looks like the endo-RNAi pathway is involved in transcription-level silencing (i.e. heterochromatin formation). Probably endo-siRNAs don't go through the stereotyped pri-, pre-, mature steps that miRNAs do.

Jason and the Argonauts is on in an hour on Turner Classic Movies. The only correspondence I can think of is maybe to refer to the primary Argonaute as Heracles, since he was only there for the first part of the adventure, after which he just hung out on an island cos he was all sad that the nymphs stole his boy-toy. I dunno if that's in the movie or not. Something tells me no.