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Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control

Lookup NU author(s): Dr Marina Danilenko, Caroline Dalgliesh, Dr Ingrid Ehrmann, Dr Alison Tyson-Capper, Dr Gavin Clowry, Professor David Elliott

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

SLM2 and Sam68 are splicing regulator paralogsthat usually overlap in function, yet only SLM2 andnot Sam68 controls the Neurexin2 AS4 exon importantfor brain function. Herein we find that SLM2and Sam68 similarly bind to Neurexin2 pre-mRNA,both within the mouse cortex and in vitro. Proteindomain-swap experiments identify a region includingthe STAR domain that differentiates SLM2and Sam68 activity in splicing target selection, andconfirm that this is not established via the variantamino acids involved in RNA contact. However, farfewer SLM2 and Sam68 RNA binding sites flank theNeurexin2 AS4 exon, compared with those flankingthe Neurexin1 and Neurexin3 AS4 exons under jointcontrol by both Sam68 and SLM2. Doubling bindingsite numbers switched paralog sensitivity, by placingthe Neurexin2 AS4 exon under joint splicing controlby both Sam68 and SLM2. Our data support amodel where the density of shared RNA binding sitesaround a target exon, rather than different paralog-specificprotein–RNA binding sites, controls functionaltarget specificity between SLM2 and Sam68on the Neurexin2 AS4 exon. Similar models mightexplain differential control by other splicing regulatorswithin families of paralogs with indistinguishable RNA binding sites.


Publication metadata

Author(s): Danilenko M, Dalgliesh C, Pagliarini V, Naro C, Ehrmann I, Feracci M, Kheirollahi-Chadegani M, Tyson-Capper A, Clowry GJ, Fort P, Dominguez C, Sette C, Elliott DJ

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2017

Volume: 45

Issue: 7

Pages: 4120–4130

Print publication date: 20/04/2017

Online publication date: 19/12/2016

Acceptance date: 08/12/2016

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/nar/gkw1277

DOI: 10.1093/nar/gkw1277


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