Work from our lab has pinpointed a central role for the splicing factor MBL/MBNL1 in circRNA biogenesis. Briefly, we found that in fly heads, the primary product from the mbl locus is the circRNA (circMbl) rather than the linear form. This circRNA consists of the second exon of mbl, which contains the start codon and encodes the N-terminal portion of the protein. In Drosophila heads, more than 90% of the molecules of RNA containing the second exon of mbl are in the circRNA form, but at least four other circRNAs and more than 15 mRNA isoforms are produced from the mbl gene. mbl is predominantly expressed in the nervous system and muscle. Interestingly, the rate of circMbl production is cell-type specific, suggesting the existence of circRNA-promoting factors. We demonstrated that one of these factors is MBL itself, as it directly regulates the generation of circMbl. This modulation requires the presence of specific MBL binding sites in the introns flanking the circularizable exon. Last but not least, we found that MBL is strongly bound to circMbl but not to mbl mRNA suggesting that this circRNA might function as a transporter and/or a sponge for MBL. Strikingly, we noticed that the same exon of MBNL1 generates circRNAs in humans and that circMbl production in mammals can also be induced by overexpression of MBL, demonstrating the conservation of this control pathway. With this as our current understanding, we aim to investigate the mutual relationship between circMbl and MBL.
Pamudurti N., Bartok O., Jens O., Ashwal-Fluss R., Stottmeister C., Ruhe L., Hanan M., Wyler E., Perez-Hernandez D., Ramberger E., Shenzis S., Samson M., Dittmar G., Landthaler M., Chekulaeva M., Rajewsky N. and Kadener S. “Translation of circRNAs”. Molecular Cell 66(1), 9-21 (2017). [Web]