Cell 159, 1365–1376 (2014)

Terminal uridylyl transferases (TUTs) catalyze the template-independent addition of uridine to the 3′ ends of many types of RNAs, but the physiological function of mRNA uridylation is not entirely clear. By employing a recently developed method called TAIL-seq, Lim et al. have now shown that two human TUTs—TUT4 and TUT7—catalyze mRNA uridylation globally. Follow-up experiments indicated that TUT4 and TUT7 preferentially act on mRNAs with short poly(A) tails (5–25 nucleotides) in vitro and in cells. The authors then determined that poly(A) binding protein C1 (PABPC1) binds to longer poly(A) tails (>25 nucleotides), preventing TUT4 and TUT7 from uridylating the 3′ ends of those mRNAs. Additional experiments revealed that the half-lives of most mRNAs were increased by an average of ∼30% when TUT4 and TUT7 were both depleted in HeLa cells, indicating that uridylation is a general mechanism by which the stabilities of mRNAs are altered. The authors also showed that knockdown of several 5′–3′ and 3′–5′ mRNA decay factors, including the 5′ revealed that the half-lives of m–DCP2 decapping complex, and a core subunit of human exosome, led to the accumulation of uridylated mRNAs with short poly(A) tails. On the basis of these results, the authors proposed a new model for uridylation-dependent mRNA decay: when mRNA decay is initiated by deadenylation, PABPs disassociate from that mRNA, enabling TUT4 and TUT7 to carry out the uridylation reaction; the nascent oligo(U) tails are detected by 5′–3′ and/or 3′–5′ mRNA decay factors, which then degrade the mRNA. Further experiments are needed to determine whether uridylation-dependent mRNA decay provides a fundamental role in the eukaryotic mRNA decay pathway.