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

Schwich, Oliver Daniel ; Blümel, Nicole ; Keller, Mario ; Wegener, Marius ; Setty, Samarth Thonta ; Brunstein, Melinda Elaine ; Poser, Ina ; Mozos, Igor Ruiz De Los ; Suess, Beatrix ; Münch, Christian ; McNicoll, François ; Zarnack, Kathi ; Müller-McNicoll, Michaela (2021)
SRSF3 and SRSF7 modulate 3′UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels.
In: Genome Biology, 22
doi: 10.1186/s13059-021-02298-y
Artikel, Bibliographie

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Kurzbeschreibung (Abstract)

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.

Typ des Eintrags: Artikel
Erschienen: 2021
Autor(en): Schwich, Oliver Daniel ; Blümel, Nicole ; Keller, Mario ; Wegener, Marius ; Setty, Samarth Thonta ; Brunstein, Melinda Elaine ; Poser, Ina ; Mozos, Igor Ruiz De Los ; Suess, Beatrix ; Münch, Christian ; McNicoll, François ; Zarnack, Kathi ; Müller-McNicoll, Michaela
Art des Eintrags: Bibliographie
Titel: SRSF3 and SRSF7 modulate 3′UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels
Sprache: Englisch
Publikationsjahr: 11 März 2021
Ort: London
Verlag: BioMed Central
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Genome Biology
Jahrgang/Volume einer Zeitschrift: 22
Kollation: 34 Seiten
DOI: 10.1186/s13059-021-02298-y
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Kurzbeschreibung (Abstract):

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.

Freie Schlagworte: SRSF3, SRSF7, APA, FIP1, CFIm, pPAS, dPAS, iCLIP, MACE-seq, 3′UTR length
ID-Nummer: Artikel-ID: 82
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Part of Springer Nature

Sachgruppe der Dewey Dezimalklassifikatin (DDC): 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Fachbereich(e)/-gebiet(e): 10 Fachbereich Biologie
10 Fachbereich Biologie > Synthetic RNA biology
Hinterlegungsdatum: 25 Sep 2024 08:49
Letzte Änderung: 25 Sep 2024 08:49
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