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Degradation of oligouridylated histone mRNAs: see UUUUU and goodbye

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Abstract During the cell cycle the expression of replication‐dependent histones is tightly coupled to DNA synthesis. Histone messenger RNA (mRNA) levels strongly increase during early S‐phase and rapidly decrease at the end of it. Here, we review the degradation of replication‐dependent histone mRNAs, a paradigm of post‐transcriptional gene regulation, in the context of processing, translation, and oligouridylation. Replication‐dependent histone transcripts are characterized by the absence of introns and by the presence of a stem‐loop structure at the 3′ end of a very short 3′ untranslated region (UTR). These features, together with a need for active translation, are a prerequisite for their rapid decay. The degradation is induced by 3′ end additions of untemplated uridines, performed by terminal uridyl transferases. Such 3′ oligouridylated transcripts are preferentially bound by the heteroheptameric LSM1‐7 complex, which also interacts with the 3′→5′ exonuclease ERI1 (also called 3′hExo). Presumably in cooperation with LSM1‐7 and aided by the helicase UPF1, ERI1 degrades through the stem‐loop of oligouridylated histone mRNAs in repeated rounds of partial degradation and reoligouridylation. Although histone mRNA decay is now known in some detail, important questions remain open: How is ceasing nuclear DNA replication relayed to the cytoplasmic histone mRNA degradation? Why is translation important for this process? Recent research on factors such as SLIP1, DBP5, eIF3, CTIF, CBP80/20, and ERI1 has provided new insights into the 3′ end formation, the nuclear export, and the translation of histone mRNAs. We discuss how these results fit with the preparation of histone mRNAs for degradation, which starts as early as these transcripts are generated. WIREs RNA 2014, 5:577–589. doi: 10.1002/wrna.1232 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > 3' End Processing RNA Turnover and Surveillance > Regulation of RNA Stability

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ERI1‐dependent degradation of the stem‐loop of oligouridylated histone mRNAs. (a) The histone messenger RNA (mRNA) 3′ end is oligouridylated by the TUTase ZCCHC11 and subsequently bound by the heteroheptameric LSM1‐7 complex. (b) ERI1 relocalizes, binds the LSM1‐7 complex and induces the degradation of the stem‐loop, which however stalls approximately 4 nt into the stem. Re‐oligouridylation and possibly UPF1 helicase activity are required to proceed. It is not exactly known at which step of histone mRNA degradation SLBP is removed from the stem‐loop. (c) The remains of the stem‐loop are removed and histone mRNA degradation progresses from the 5′ as well as from the 3′ end.
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Coupling of replication stress to histone messenger RNA (mRNA) degradation. (a) Replication fork stalling at the end of S‐phase or after hydroxyurea treatment of cells causes DNA damage and UPF1 phosphorylation by ATR/DNA‐PK. (b) Nuclear export and transport of phosho‐UPF1 to the 3′ side of the histone mRNA stem‐loop by the ribosomes. In analogy to NMD phosphorylated UPF1 transiently interacts with CBP80. As active translation is a requirement for histone mRNA degradation and increased phospho‐UPF1 was detected in polysomal compared to subpolysomal fractions, we speculate that phospho‐UPF1 may be transported by ribosomes to the 3′ end from where it can bind to SLBP at the stem‐loop. Phospho‐UPF1 inhibits translation initiation by interaction with eIF3e. It can also initiate 5′→3′ mRNA degradation by the recruitment of decapping factors (not shown). We speculate that UPF1 may potentially interact with ZCCHC11 to induce oligouridylation of the histone mRNA.
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Initiation of histone messenger RNA (mRNA) translation. (a) Required complexes to initiate translation of histone mRNAs. (b) Histone mRNP in the pioneer round of translation. CTIF interacts with CBP80 of the CBC at the cap structure (dark green dot). A SLIP1 dimer makes protein–protein contacts with stem‐loop‐bound SLBP and ERI1 at the 3′ end of the histone mRNA. CTIF binds to SLBP to form a circular histone mRNA structure. SLIP1 and CTIF both contribute to recruit eIF3g and thereby the 43S PIC. The 43S PIC scans the sequence for a start codon, preferably in the context of a Kozak sequence. Subsequent recruitment of the 60S subunit creates a functional 80S ribosome. More than one ribosome can occupy an mRNA in the pioneer round of translation, during which the cap is bound by the CBC. In contrast to other mRNAs the minority of histone mRNAs exchanges the CBC for eIF4e later in translation. Therefore, this situation is not depicted. Start codon (AUG). PIC, pre‐initiation complex.
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Histone messenger RNA (mRNA) 3′ end formation and nuclear export. (a) Transcription of a histone pre‐mRNA (dark green line), including a cap structure (dark green dot) and a histone downstream element (HDE), is depicted. The RNA backbone of the histone mRNA stem‐loop is shown in a planar projection based on a recently published crystal structure (dark green line, right side). Both, co‐transcriptional binding of SLBP to the stem‐loop and base‐pairing of the U7 snRNA with the HDE contribute to the formation of a multi‐protein complex (not shown), including CPSF73. The endonucleolytic activity of CPSF73 acts to create the processed 3′ end of the histone mRNA. ERI1‐binding to the histone stem‐loop is U7 snRNA‐dependent and likely occurs subsequent to HDE cleavage. Binding of CBP80 to CBP20 induces conformation changes in CBP20 (not shown) and an increased binding affinity for the cap structure. (b) SLBP and ERI1 have resumed their respective positions 5′ and 3′ of the stem‐loop. Both proteins and the stem‐loop are drawn to scale. ERI1 trims two nucleotides off the histone mRNA 3′ end. A SLIP1 dimer bridges the interaction between the essential mRNA export factor DBP5 and SLBP. The nuclear export of the histone mRNP through the nuclear pore complex (NPC) may be mediated by DBP5. CBC, cap‐binding complex; RNA pol., RNA polymerase.
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Processing > 3′ End Processing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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