Oral Presentation 41st Lorne Genome Conference 2020

Nuclear Export of Circular RNA (#16)

Linh Ngo 1 , Toby Williams 1 , Kirsty Carey 1 , Greg Goodall 2 , Vihandha Wickramasinghe 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Centre for Cancer Biology, Adelaide, SA, Australia

Circular RNAs (circRNAs), which can function as regulators of gene expression, are formed by back-splicing of precursor mRNAs in the nucleus. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here, we identify the pathway involved in the nuclear export of circRNA. Unexpectedly, circRNAs are not exported by canonical mRNA export pathways. Instead, circRNA export requires Ran-GTP, Exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter, CRM1, selectively increases nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Analysis of nuclear circRNA binding proteins reveals that interaction of IGF2BP1 with circRNA is enhanced by Ran-GTP. Depletion of Exportin-2 inhibits nuclear export of circRNA, while formation of an Exportin-2 circRNA export complex requires Ran-GTP and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Exportin-2 to export circRNAs in a mechanism analogous to protein export, rather than mRNA export.