Coordination of Adenosine to Inosine Editing and mRNA Splicing
Evolutionary Cell and Developmental Biology (Zoology)
Final Report Abstract
Alternative splicing and adenosine to inosine RNA editing (A to I editing) are the two most important factors diversifying the mammalian transcriptome. Alternative splicing occurs on more than 90% of human multi-exon genes. For A to I editing on the other hand over 2 million editing sites have been identified. Both processes occur co-transcriptionally and have mutual impact on each other. A to I editing can only occur on double-stranded RNAs. Frequently the double-strand required for editing is formed between an exon and an intron. The major finding of the project is that the efficiency or the „speed“ of the splicing reaction of particular pre-mRNAs can control the extent of A to I editing if the editing-competent duplex is formed between exon and intron. We saw an increase in editing levels upon reduced splicing efficiency in this case. This can be explained by the binding properties of the enzymes catalyzing the editing reaction. Since these ADAR (Adenosine deaminase acting on RNA) enzymes bind to double-stranded RNA in this case the duration of binding is increased if splicing is „slow“. This explains the increase in editing levels since the editing enzymes have more time for catalysis. Consequently, for editing sites harboring the editing-competent stem in the exon itself no change in editing levels upon reduced spicing efficiency was observed. Surprisingly in the course of the project, we also observed strong differences in pre-mRNA editing levels and mRNA editing levels. Subsequent analysis revealed that differential processing may explain these differences. In sum, we have identified splicing as a major factor controlling editing levels. This may also be interesting with respect to alternative splicing factors. Different alternative splicing regulators may not only control splicing but have an impact on editing levels as well. However, further studies are required to verify if alternative splicing factors can also modulate and control editing levels of particular substrates. Since de-regulation of editing levels has been associated with various pathologies like cancer, depression, and epilepsy the identification of mechanisms - like splicing - regulating editing levels and controlling editing is very important.
Publications
- (2016) Adenosine to Inosine editing frequency controlled by splicing efficiency. NAR Nucleic Acids Research, Volume 44, Issue 13, 27 July 2016, Pages 6398–6408
Licht K, Kapoor U, Mayerhofer E, Jantsch MF
(See online at https://doi.org/10.1093/nar/gkw325) - (2016) Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications. JCB. 213(1):15-22
Licht K and Jantsch MF
(See online at https://doi.org/10.1083/jcb.201511041) - (2016) The dynamic epitranscriptome: A to I editing modulates genetic information. Chromosoma. 125(1):51-63
Tajaddod M, Jantsch MF, and Licht K
(See online at https://doi.org/10.1007/s00412-015-0526-9) - (2016). Co-transcriptional interplay: Splicing controls the extent of Adenosine to Inosine Editing. 21st Annual Meeting of the RNA society. Kyoto (Japan)
Licht K, Kapoor U, Mayerhofer E, and Jantsch MF
