Alu RNA fold links splicing with signal recognition particle proteins

Author:

Borovská Ivana1ORCID,Vořechovský Igor2ORCID,Královičová Jana13ORCID

Affiliation:

1. Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences , Bratislava 840 05 , Slovak Republic

2. Faculty of Medicine, University of Southampton, HDH, MP808 , Southampton SO16 6YD, United Kingdom

3. Institute of Zoology, Slovak Academy of Sciences , Bratislava  845 06, Slovak Republic

Abstract

Abstract Transcriptomic diversity in primates was considerably expanded by exonizations of intronic Alu elements. To better understand their cellular mechanisms we have used structure-based mutagenesis coupled with functional and proteomic assays to study the impact of successive primate mutations and their combinations on inclusion of a sense-oriented AluJ exon in the human F8 gene. We show that the splicing outcome was better predicted by consecutive RNA conformation changes than by computationally derived splicing regulatory motifs. We also demonstrate an involvement of SRP9/14 (signal recognition particle) heterodimer in splicing regulation of Alu-derived exons. Nucleotide substitutions that accumulated during primate evolution relaxed the conserved left-arm AluJ structure including helix H1 and reduced the capacity of SRP9/14 to stabilize the closed Alu conformation. RNA secondary structure-constrained mutations that promoted open Y-shaped conformations of the Alu made the Alu exon inclusion reliant on DHX9. Finally, we identified additional SRP9/14 sensitive Alu exons and predicted their functional roles in the cell. Together, these results provide unique insights into architectural elements required for sense Alu exonization, identify conserved pre-mRNA structures involved in exon selection and point to a possible chaperone activity of SRP9/14 outside the mammalian signal recognition particle.

Funder

VEGA

Slovak Research and Development Agency

Publisher

Oxford University Press (OUP)

Subject

Genetics

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