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Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay

Nature Structural & Molecular Biology volume 20, pages 73–81 (2013)Cite this article

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Abstract

The exoRNase Eri1 inhibits RNA interference and trims the 5.8S rRNA 3′ end. It also binds to the stem-loop of histone mRNAs, but the functional importance of this interaction remains elusive. Histone mRNAs are normally degraded at the end of S phase or after pharmacological inhibition of replication. Both processes are impaired in Eri1-deficient mouse cells, which instead accumulate oligouridylated histone mRNAs. Eri1 trims the mature histone mRNAs by two unpaired nucleotides at the 3′ end but stalls close to the double-stranded stem. Upon oligouridylation of the histone mRNA, the Lsm1–7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, whose catalytic activity is then able to degrade the stem-loop in a stepwise manner. These data demonstrate how degradation of histone mRNAs is initiated when 3′ oligouridylation creates a cis element that enables Eri1 to process the double-stranded stem-loop structure.

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Figure 1: Eri1 is required for the degradation of replication-dependent histone mRNAs.
Figure 2: Eri1 binds, degrades and trims the 3′ end of cellular histone mRNAs.
Figure 3: Eri1 degrades oligouridylated histone mRNAs.
Figure 4: Impaired cell cycle–dependent degradation of oligouridylated histone mRNAs in Eri1-deficient cells.
Figure 5: Oligouridylation of histone mRNA represses translation and promotes Eri1-mediated degradation.
Figure 6: Lsm1 binds to Eri1 and oligouridylated Hist1h2ak mRNA after hydroxyurea treatment.
Figure 7: Eri1 degrades through the stem-loop in consecutive cycles of oligouridylation and partial degradation.

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Acknowledgements

We would like to thank W. Pastor and A. Rao (La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA) for providing the FLAG-HA-hERI1 construct. We thank D. Repsilber (Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany) for advice on statistical analyses. R. Lührmann (Max Planck Institute for Biophysical Chemistry, Göttingen, Germany) kindly provided anti-Lsm1 antibodies. This work was supported by the German Research Foundation (DFG HE 3359/3-1 to V.H.).

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Author notes

  1. Nicola Rath

    Present address: Present address: Beatson Institute for Cancer Research, Glasgow, UK.,

  2. Nicola Rath and Gitta A Heinz: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Immunology, Helmholtz Zentrum München, München, Germany

    Kai P Hoefig, Nicola Rath, Gitta A Heinz, Christine Wolf, Jasmin Dameris, Elisabeth Kremmer & Vigo Heissmeyer

  2. Research Unit Gene Vectors, Helmholtz Zentrum München, München, Germany

    Aloys Schepers

  3. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA

    K Mark Ansel

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Contributions

V.H. and K.M.A. conceived of the project idea. K.P.H. and V.H. designed and K.P.H. performed most of the experiments with help from C.W., J.D. and A.S. N.R. carried out the reconstitution experiments. N.R. and G.A.H. performed the immunoprecipitation experiments, and E.K. generated the monoclonal antibodies. K.P.H., V.H. and K.M.A. discussed the data, and K.P.H. and V.H. wrote the manuscript.

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Correspondence to Vigo Heissmeyer.

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Hoefig, K., Rath, N., Heinz, G. et al. Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay. Nat Struct Mol Biol 20, 73–81 (2013). https://doi.org/10.1038/nsmb.2450

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