Abstract
Cytoplasmic polyadenylation-induced translation controls germ cell development1,2, neuronal synaptic plasticity3-5, and cellular senescence6,7, a tumor-suppressor mechanism that limits the replicative lifespan of cells8,9 . The cytoplasmic polyadenylation element binding protein (CPEB) promotes polyadenylation by nucleating a group of factors including defective in germline development 2 (Gld2), a non-canonical poly(A) polymerase10,11, on specific mRNA 3’ untranslated regions (UTRs). Because CPEB regulation of p53 mRNA polyadenylation/translation is necessary for cellular senescence in primary human diploid fibroblasts6, we surmised that Gld2 would be the enzyme responsible for poly(A) addition. Here, we show that depletion of Gld2 surprisingly promotes rather than inhibits p53 mRNA polyadenylation/translation, induces premature senescence, and enhances the stability of CPEB mRNA. The CPEB 3’UTR contains two miR-122 binding sites, which when deleted, elevate mRNA translation, as does an antagomir of miR-122. Although miR-122 is thought to be liver-specific, it is present in primary fibroblasts and destabilized by Gld2 depletion. Gld4, a second non-canonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner. Thus, translational regulation of p53 mRNA and cellular senescence is coordinated by Gld2/miR-122/CPEB/Gld4.
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