Structural Requirements for A-to-I RNA Editing in the Mammalian Brain
2016 (English)Manuscript (preprint) (Other academic)
The transcriptome of the mammalian brain is subjected to RNA modification through adenosine to inosine (A-to-I) editing at a substantial number of sites. This is an essential event that plays a significant role for neuronal function in neurotransmission. The excitatory AMPA glutamate receptors subunit A2 (GluA2) is subjected to editing at several sites in its transcript. Editing at one site in the GluA2 transcript changes the readout of the protein in the ion selection filter of the inner channel pore and renders the receptor permeability to Ca2+. Since inosine is read as a guanosine during translation, editing at this site in GluA2 gives rise to a glutamine to an arginine change (Q/R). This is the most efficient site of editing known, where almost 100% of all transcripts are edited. A double stranded RNA (dsRNA) structure is a requisite for A-to-I editing but it is not clear why this substrate is so extraordinarily efficiently edited. We have discovered that the Q/R editing site in GluA2 requires an editing inducer element (EIE) in the downstream intron in order to be efficiently edited. We further show that this cis-acting inducer element is independent of its location, upstream or downstream, from the editing site. We have previously shown that the Gabra-3 transcript coding for the a3 subunit of the GABAA receptor requires an EIE to be efficiently edited. Common between these EIEs is a long double stranded stem structure but their sequences are not homologous. We also show that the EIEs can replace each other in the induction of efficient editing. We propose a model where two regions of dsRNA are required for efficient editing: first, a long dsRNA to recruit the ADAR enzyme and increase the local concentration of the deaminase and then a shorter less stable duplex required to perform the catalysis. We further show that the efficiently edited kainate glutamate receptor subunit GluK2 also holds an EIE and propose that this is a general requisite for most site selective editing within coding sequence. This discovery will change the view of how we define a substrate for A-to-I editing that will be important in the discovery of novel editing sites as well as explaining cases of altered editing in relation to disease.
Place, publisher, year, edition, pages
2016. , 59 p.
RNA editing, adenosine deamination, Glutamate receptor, ADAR
Biochemistry and Molecular Biology
Research subject Molecular Bioscience
IdentifiersURN: urn:nbn:se:su:diva-135596OAI: oai:DiVA.org:su-135596DiVA: diva2:1046833