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Cell. 2014 Sep 25;159(1):134-147. doi: 10.1016/j.cell.2014.09.001. Epub 2014 Sep 18.

Complementary sequence-mediated exon circularization.

Author information

1
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
2
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
3
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4
Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
5
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: linglingchen@sibcb.ac.cn.
6
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: liyang@picb.ac.cn.

Abstract

Exon circularization has been identified from many loci in mammals, but the detailed mechanism of its biogenesis has remained elusive. By using genome-wide approaches and circular RNA recapitulation, we demonstrate that exon circularization is dependent on flanking intronic complementary sequences. Such sequences and their distribution exhibit rapid evolutionary changes, showing that exon circularization is evolutionarily dynamic. Strikingly, exon circularization efficiency can be regulated by competition between RNA pairing across flanking introns or within individual introns. Importantly, alternative formation of inverted repeated Alu pairs and the competition between them can lead to alternative circularization, resulting in multiple circular RNA transcripts produced from a single gene. Collectively, exon circularization mediated by complementary sequences in human introns and the potential to generate alternative circularization products extend the complexity of mammalian posttranscriptional regulation.

PMID:
25242744
DOI:
10.1016/j.cell.2014.09.001
[Indexed for MEDLINE]
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