Serine/arginine-rich splicing factor 3 (Pre-mRNA-splicing factor SRP20) (Splicing factor, arginine/serine-rich 3) [SFRS3] [SRP20]
Down-regulated splicing factor SRSF3 is known to promote cellular senescence, an important biological process in preventing cancer and contributing to individual aging, via its alternative splicing dependent function in human cells. Here we discovered alternative polyadenylation (APA) dependent function of SRSF3 as a novel mechanism explaining SRSF3 downregulation induced cellular senescence. Knockdown of [i]SRSF3[/i] resulted in preference usage of proximal poly(A) sites and thus global shortening of 3' untranslated regions (3' UTRs) of mRNAs. [i]SRSF3[/i]-depletion also induced senescence-related phenotypes in both human and mouse cells. These 3' UTR shortened genes were enriched in senescence-associated pathways. Shortened 3' UTRs tended to produce more proteins than the longer ones. Simulating the effects of 3' UTR shortening by overexpression of three candidate genes ([i]PTEN, PIAS1[/i] and [i]DNMT3A[/i]) all led to senescence-associated phenotypes. Mechanistically, SRSF3 has higher binding density near proximal poly(A) site than distal one in 3' UTR shortened genes. Further, upregulation of [i]PTEN[/i] by either ectopic overexpression or [i]SRSF3[/i]-knockdown induction both led to reduced phosphorylation of AKT and ultimately senescence-associated phenotypes. We revealed for the first time that reduced SRSF3 expression could promote cellular senescence through its APA-dependent function, largely extending our mechanistic understanding in splicing factor regulated cellular senescence.
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