The transcriptional terminator XRN2 and the RNA binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer

Alternative cleavage and polyadenylation (APA) of pre-mRNAs yields multiple transcripts differing in their 3' end and its regulation is often aberrant in human cancers, including prostate cancer (PC). In this study, we have uncovered a novel mechanism of APA regulation which impinges on the functional interaction between the 5'-3' exonuclease XRN2 and the A/U-rich motif RNA binding protein Sam68 in PC cells. XRN2 promotes recruitment of Sam68 to its target transcripts, where it competes with the cleavage and polyadenylation specificity factor (CPSF) for the recognition of the AAUAAA core polyadenylation signal (PAS) motif. In particular, the Sam68/XRN2 complex suppresses the usage of strong canonical PASs at distal ends of genes and, consequently, promotes the usage of suboptimal proximal PASs. We have profiled the global effect of Sam68 and XRN2 on alternative polyadenylation by 3’READS-seq analysis using RNA isolated from LNCaP cells after 48 hours of RNAi, with 2 biological replicates.