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Nature. 2019 Sep;573(7774):375-380. doi: 10.1038/s41586-019-1523-6. Epub 2019 Sep 4.

A unified mechanism for intron and exon definition and back-splicing.

Author information

1
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
2
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
3
Electron Imaging Center for Nanomachines, UCLA, Los Angeles, CA, USA.
4
Biophysics Program, Stanford University, Stanford, CA, USA.
5
Department of Biochemistry, Stanford University, Stanford, CA, USA.
6
Department of Physics, Stanford University, Stanford, CA, USA.
7
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA. hong.zhou@ucla.edu.
8
Electron Imaging Center for Nanomachines, UCLA, Los Angeles, CA, USA. hong.zhou@ucla.edu.
9
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. rui.zhao@cuanschutz.edu.
10
RNA Bioscience Initiative, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. rui.zhao@cuanschutz.edu.

Abstract

The molecular mechanisms of exon definition and back-splicing are fundamental unanswered questions in pre-mRNA splicing. Here we report cryo-electron microscopy structures of the yeast spliceosomal E complex assembled on introns, providing a view of the earliest event in the splicing cycle that commits pre-mRNAs to splicing. The E complex architecture suggests that the same spliceosome can assemble across an exon, and that it either remodels to span an intron for canonical linear splicing (typically on short exons) or catalyses back-splicing to generate circular RNA (on long exons). The model is supported by our experiments, which show that an E complex assembled on the middle exon of yeast EFM5 or HMRA1 can be chased into circular RNA when the exon is sufficiently long. This simple model unifies intron definition, exon definition, and back-splicing through the same spliceosome in all eukaryotes and should inspire experiments in many other systems to understand the mechanism and regulation of these processes.

PMID:
31485080
DOI:
10.1038/s41586-019-1523-6

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