The RNA binding protein quaking regulates formation of circRNAs

Simon J Conn; Katherine A Pillman; John Toubia; Vanessa M Conn; Marika Salmanidis; Caroline A Phillips; Suraya Roslan; Andreas W Schreiber; Philip A Gregory; Gregory J Goodall

doi:10.1016/j.cell.2015.02.014

The RNA binding protein quaking regulates formation of circRNAs

Cell. 2015 Mar 12;160(6):1125-34. doi: 10.1016/j.cell.2015.02.014.

Affiliations

¹ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia.
² Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA 5000, Australia.
³ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia.
⁴ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia; ACRF Cancer Genomics Facility, SA Pathology, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia.
⁵ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: greg.goodall@health.sa.gov.au.

PMID: 25768908
DOI: 10.1016/j.cell.2015.02.014

Abstract

Circular RNAs (circRNAs), formed by non-sequential back-splicing of pre-mRNA transcripts, are a widespread form of non-coding RNA in animal cells. However, it is unclear whether the majority of circRNAs represent splicing by-products without function or are produced in a regulated manner to carry out specific cellular functions. We show that hundreds of circRNAs are regulated during human epithelial-mesenchymal transition (EMT) and find that the production of over one-third of abundant circRNAs is dynamically regulated by the alternative splicing factor, Quaking (QKI), which itself is regulated during EMT. Furthermore, by modulating QKI levels, we show the effect on circRNA abundance is dependent on intronic QKI binding motifs. Critically, the addition of QKI motifs is sufficient to induce de novo circRNA formation from transcripts that are normally linearly spliced. These findings demonstrate circRNAs are both purposefully synthesized and regulated by cell-type specific mechanisms, suggesting they play specific biological roles in EMT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Epithelial-Mesenchymal Transition*
Exons
Humans
Introns
RNA / metabolism*
RNA Splicing
RNA, Circular
RNA-Binding Proteins / metabolism*

Substances

QKI protein, human
RNA, Circular
RNA-Binding Proteins
RNA