Model of histone mRNA degradation. (A) Role of TUT7 and 3′hExo in histone mRNA metabolism and degradation. (a–c) The processed histone mRNA has a 5 nt 3′ tail (a) which is trimmed by 3′hExo to 3 nts (b). If there is additional trimming, a TUTase adds uridine to restore tail to 3 nt (c). (d–h) When DNA synthesis is inhibited in S-phase or at the end of S-phase, 3′hExo degrades into the stem (d), and long U-tails are added by TUT7 (e). It is likely that repeated cycles of degradation and uridylation occur since intermediates at each nt are readily detected (Figs. 2–4). SLBP is removed and processive degradation, likely by the exosome, is activated (f). Degradation is stalled by the terminating ribosome and the RNA is uridylated (g). The exosome can proceed through the ribosome and then ultimately through the ORF with uridylated intermediates (h). Note that the initial intermediates with U-tails added in the stem likely can form a stem–loop with the U's pairing with the two G's on the 5′ side of the stem, which is then able to bind SLBP (PE Lackey and WF Marzluff, unpubl.). Once the U-tail is long enough to bind Lsm 1–7 then it can no longer bind SLBP. It is likely that TUT7 specifically interacts with the 3′ end of histone mRNA bound to SLBP to account for this specificity. (B) Schematic of the intermediate just before removal of SLBP (between e and f in panel A). Lsm 1–7 binds to long U-tails (>7 nt) added to intermediates in the stem, and interacts directly with SLBP and 3′hExo (Lyons et al. 2014). Together with Upf1, which is bound to the terminating ribosome and the 3′-UTR after inhibition of DNA replication, SLBP is removed, allowing processive degradation until the terminating ribosome is reached.
