More than half of mammalian genes generate multiple messenger RNA isoforms that differ in their 3′ untranslated regions (3′ UTRs) and therefore in regulatory sequences, often associated with cell proliferation and cancer; however, the mechanisms coordinating alternative 3′-UTR processing for specific mRNA populations remain poorly defined. Here we report that the cytoplasmic polyadenylation element binding protein 1 (CPEB1), an RNA-binding protein that regulates mRNA translation, also controls alternative 3′-UTR processing. CPEB1 shuttles to the nucleus, where it co-localizes with splicing factors and mediates shortening of hundreds of mRNA 3′ UTRs, thereby modulating their translation efficiency in the cytoplasm. CPEB1-mediated 3′-UTR shortening correlates with cell proliferation and tumorigenesis. CPEB1 binding to pre-mRNAs not only directs the use of alternative polyadenylation sites, but also changes alternative splicing by preventing U2AF65 recruitment. Our results reveal a novel function of CPEB1 in mediating alternative 3′-UTR processing, which is coordinated with regulation of mRNA translation, through its dual nuclear and cytoplasmic functions.
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