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

Autor: Schwich OD; Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt, Germany., Blümel N; Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt, Germany., Keller M; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt, Germany.; Faculty of Biological Sciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany., Wegener M; Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt, Germany., Setty ST; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt, Germany., Brunstein ME; Institute of Biochemistry II, Medical School, Goethe University Frankfurt, Sandhofstr. 2-4, 60528, Frankfurt am Main, Germany., Poser I; Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany., Mozos IRL; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK., Suess B; Department of Biology, Technical University Darmstadt, Schnittspahnstr. 10, 64287, Darmstadt, Germany., Münch C; Institute of Biochemistry II, Medical School, Goethe University Frankfurt, Sandhofstr. 2-4, 60528, Frankfurt am Main, Germany., McNicoll F; Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt, Germany., Zarnack K; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438, Frankfurt, Germany. kathi.zarnack@bmls.de.; Faculty of Biological Sciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany. kathi.zarnack@bmls.de., Müller-McNicoll M; Institute for Molecular Bio Science, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt, Germany. mueller-mcnicoll@bio.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2021 Mar 11; Vol. 22 (1), pp. 82. Date of Electronic Publication: 2021 Mar 11.
DOI: 10.1186/s13059-021-02298-y
Abstrakt: 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.
Databáze: MEDLINE
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