TY  - JOUR
A1  - Schwich, Oliver Daniel
A1  - Blümel, Schwich
A1  - Keller, Mario
A1  - Wegener, Marius
A1  - Setty, Samarth Thonta
A1  - Brunstein, Melinda Elaine
A1  - Poser, Ina
A1  - Ruiz de los Mozos, Igor
A1  - Süß, Beatrix
A1  - Münch, Christian
A1  - McNicoll, François
A1  - Zarnack, Katharina
A1  - Müller-McNicoll, Michaela
T1  - SRSF3 and SRSF7 modulate 3′UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels
T2  - Genome biology
N2  - 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.
KW  - SRSF3
KW  - SRSF7
KW  - APA
KW  - FIP1
KW  - CFIm
KW  - pPAS
KW  - dPAS
KW  - iCLIP
KW  - MACE-seq
KW  - 3′UTR length
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/58901
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-589014
SN  - 1474-760X
VL  - 22
IS  - 82
SP  - 1
EP  - 34
ER  -