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

The selection of polyadenylation signals defines 3 ' UTR length. The authors find that MYC alters the expression of factors that repress strong polyadenylation signals at the distal end of genes, boosting usage of suboptimal, proximal polyadenylation signals and promoting the translation of cell cycle-related genes. Alternative polyadenylation (APA) yields transcripts differing in their 3 '-end, and its regulation is altered in cancer, including prostate cancer. Here we have uncovered a mechanism of APA regulation impinging on the interaction between the exonuclease XRN2 and the RNA-binding protein Sam68, whose increased expression in prostate cancer is promoted by the transcription factor MYC. Genome-wide transcriptome profiling revealed a widespread impact of the Sam68/XRN2 complex on APA. XRN2 promotes recruitment of Sam68 to its target transcripts, where it competes with the cleavage and polyadenylation specificity factor for binding to strong polyadenylation signals at distal ends of genes, thus promoting usage of suboptimal proximal polyadenylation signals. This mechanism leads to 3 ' untranslated region shortening and translation of transcripts encoding proteins involved in G1/S progression and proliferation. Thus, our findings indicate that the APA program driven by Sam68/XRN2 promotes cell cycle progression and may represent an actionable target for therapeutic intervention.

Automated summary

The selection of polyadenylation signals and alternative polyadenylation (APA) play important roles in gene expression regulation. This study uncovers a mechanism of APA regulation involving the interaction between XRN2 exonuclease and Sam68 RNA-binding protein. The increased expression of Sam68 in prostate cancer, promoted by MYC, leads to the usage of suboptimal proximal polyadenylation signals and enhances cell cycle-related gene translation. This finding suggests that the Sam68/XRN2-driven APA program may be a potential target for therapeutic strategies.