Alternative polyadenylation dependent function of splicing factor SRSF3 contributes to cellular senescence

Down-regulated splicing factor SRSF3 is known to modulate cellular senescence 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 SRSF3 (SRSF3-KD) resulted in preference of proximal poly(A) (pA) sites and thus global shortening of 3′ untranslated regions (3′ UTRs) of mRNAs. SRSF3-KD 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 (PTEN, PIAS1 and DNMT3A) all led to senescence-associated phenotypes. Mechanistically, SRSF3 has higher binding density near proximal pA site than distal one in 3′ UTR shortened genes. Further, upregulation of PTEN by either ectopic overexpression or SRSF3-KD induction both led to reduced phosphorylation of AKT and ultimately senescence-associated phenotypes.