SRSF3 and SRSF7 modulate 3′UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels

  • Background: Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3′ untranslated regions (3′UTRs). We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained unknown. Results: Here we combine iCLIP and 3′-end sequencing and find that SRSF3 and SRSF7 bind upstream of proximal PASs (pPASs), but they exert opposite effects on 3′UTR length. SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, generating short 3′UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3′UTRs directly by counteracting SRSF7, but also indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3′UTRs are shortened. The indirect SRSF3 targets are particularly sensitive to low CFIm levels, because here CFIm serves a dual function; it enhances dPAS and inhibits pPAS usage by binding immediately downstream and assembling unproductive cleavage complexes, which together promotes long 3′UTRs. Conclusions; We demonstrate that SRSF3 and SRSF7 are direct modulators of pPAS usage and show how small differences in the domain architecture of SR proteins can confer opposite effects on pPAS regulation.

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Author:Oliver Daniel Schwich, Schwich Blümel, Mario Keller, Marius Wegener, Samarth Thonta Setty, Melinda Elaine Brunstein, Ina Poser, Igor Ruiz de los Mozos, Beatrix SüßGND, Christian MünchORCiD, François McNicoll, Katharina ZarnackORCiDGND, Michaela Müller-McNicollORCiD
Parent Title (English):Genome biology
Document Type:Article
Date of Publication (online):2021/03/11
Date of first Publication:2021/03/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/10/06
Tag:3′UTR length; APA; CFIm; FIP1; MACE-seq; SRSF3; SRSF7; dPAS; iCLIP; pPAS
Page Number:34
First Page:1
Last Page:34
Institutes:Biowissenschaften / Biowissenschaften
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0