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.

Pieraccioli, M., Caggiano, C., Mignini, L., Zhong, C., Babini, G., Lattanzio, R., et al. (2022). The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 29(11), 1101-1112 [10.1038/s41594-022-00853-0].

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

Di Stasi S
Membro del Collaboration Group
;
Bielli P
Membro del Collaboration Group
2022-11-07

Abstract

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.
7-nov-2022
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/24 - UROLOGIA
English, Middle (1100-1500)
Con Impact Factor ISI
MeSH 3' Untranslated Regions; Cell Cycle; Cell Cycle Proteins; Exoribonucleases; Humans; Male; Polyadenylation; Prostatic Neoplasms; RNA-Binding Proteins EMTREE drug terms cell cycle protein; exoribonuclease; RNA binding protein; XRN2 protein, human EMTREE medical terms 3' untranslated region; cell cycle; genetics; human; male; metabolism; polyadenylation; prostate tumor
Pieraccioli, M., Caggiano, C., Mignini, L., Zhong, C., Babini, G., Lattanzio, R., et al. (2022). The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 29(11), 1101-1112 [10.1038/s41594-022-00853-0].
Pieraccioli, M; Caggiano, C; Mignini, L; Zhong, C; Babini, G; Lattanzio, R; Di Stasi, S; Tian, B; Sette, C; Bielli, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/311638
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