Abstract

Replication dependent (RD) core histone mRNA produced during S-phase is the only known protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. We report cellular, genetic, biochemical, substrate selectivity, and crystallographic studies providing evidence that an additional endoribonuclease, MBL domain containing protein 1 (MBLAC1), is selective for 3' processing of RD histone pre-mRNA during the S-phase of the cell cycle. Depletion of MBLAC1 in cells significantly affects cell cycle progression thus identifying MBLAC1 as a new type of S-phase specific cancer target.

Data availability

Diffraction data have been deposited in PDB under the accession code 4V0H.ChrRNA-seq data generated during this study can be accessed at the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=kncnwiswrpapngj&acc=GSE94686

The following data sets were generated

Article and author information

Author details

  1. Ilaria Pettinati

    Department of Chemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  2. Pawel Grzechnik

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    No competing interests declared.
  3. Claudia Ribeiro de Almeida

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Jurgen Brem

    Department of Chemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Michael A McDonough

    Department of Chemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  6. Somdutta Dhir

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  7. Nick J Proudfoot

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    nicholas.proudfoot@path.ox.ac.uk
    Competing interests
    Nick J Proudfoot, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8646-3222
  8. Christopher J Schofield

    Department of Chemistry, University of Oxford, Oxford, United Kingdom
    For correspondence
    christopher.schofield@chem.ox.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0290-6565

Funding

Wellcome (107928/Z/15/Z)

  • Nick J Proudfoot

Medical Research Council

  • Christopher J Schofield

Wellcome

  • Christopher J Schofield

Cancer Research UK

  • Christopher J Schofield

Biotechnology and Biological Sciences Research Council

  • Christopher J Schofield

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2018, Pettinati et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ilaria Pettinati
  2. Pawel Grzechnik
  3. Claudia Ribeiro de Almeida
  4. Jurgen Brem
  5. Michael A McDonough
  6. Somdutta Dhir
  7. Nick J Proudfoot
  8. Christopher J Schofield
(2018)
Biosynthesis of histone messenger RNA employs a specific 3' end endonuclease
eLife 7:e39865.
https://doi.org/10.7554/eLife.39865

Share this article

https://doi.org/10.7554/eLife.39865

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