CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation

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Abstract
Messenger RNAs are capped at their 3′ ends by a non-templated run of adenines — the polyA tail — that enhances their translation. The polyA polymerase Gld2 is guided to 3′ untranslated regions by the sequence-specific CPEB protein. Richter and colleagues have now found that the p53 tumour suppressor is not simply polyadenylated by Gld2. Rather, Gld2 can add a single A to the miR-122 microRNA, thereby stabilizing it. This adenylated miR-122/RISC complex then downregulates CPEB expression by binding target sites in its 3′ untranslated region. If CPEB is not downregulated by miR-122, CPEB binds the p53 3′ untranslated region and recruits a different polyA polymerase, Gld4. The data demonstrate a previously unknown hierarchy of translational control of p53 mRNA leading to cellular senescence. Cytoplasmic polyadenylation-induced translation controls germ cell development1,2, neuronal synaptic plasticity3,4,5 and cellular senescence6,7, a tumour-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) polymerase10,11,12, on specific messenger RNA (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.