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

Alternative polyadenylation (APA) yields transcripts differing in their 3′-end,\r\nand its regulation is altered in cancer, including prostate cancer. Here we\r\nhave uncovered a mechanism of APA regulation impinging on the interaction\r\nbetween the exonuclease XRN2 and the RNA-binding protein Sam68, whose\r\nincreased expression in prostate cancer is promoted by the transcription\r\nfactor MYC. Genome-wide transcriptome profiling revealed a widespread\r\nimpact of the Sam68/XRN2 complex on APA. XRN2 promotes recruitment\r\nof Sam68 to its target transcripts, where it competes with the cleavage and\r\npolyadenylation specificity factor for binding to strong polyadenylation\r\nsignals at distal ends of genes, thus promoting usage of suboptimal proximal\r\npolyadenylation signals. This mechanism leads to 3′ untranslated region\r\nshortening and translation of transcripts encoding proteins involved in\r\nG1/S progression and proliferation. Thus, our findings indicate that the APA\r\nprogram driven by Sam68/XRN2 promotes cell cycle progression and may\r\nrepresent an actionable target for therapeutic intervention.