Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.
Nicola de PriscoCaitlin FordNathan D ElrodWinston LeeLauren C TangKai-Lieh HuangAi LinPing JiVenkata S JonnakutiLia BoyleMaximilian CabajSalvatore BottaKatrin ÕunapKarit ReinsonMonica Hsiung WojcikJill Anne RosenfeldWeimin BiKristian TvetenTrine PrescottThorsten GerstnerAudrey SchroederChin-To FongJaya K George-AbrahamCatherine A BuchananAndrea Hanson-KahnJonathan A BernsteinAikaterini A NellaWendy K ChungVicky L BrandtMarko JovanovicKimara L TargoffHari Krishna YalamanchiliEric J WagnerVincenzo A GennarinoPublished in: Science advances (2023)
Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.