RESEARCH ARTICLE Biosynthesis of histone messenger RNA employs a specific 3’ end endonuclease Ilaria Pettinati1, Pawel Grzechnik2, Claudia Ribeiro de Almeida3, Jurgen Brem1, Michael A McDonough1, Somdutta Dhir3, Nick J Proudfoot3*, Christopher J Schofield1* 1Department of Chemistry, University of Oxford, Oxford, United Kingdom; 2School of Biosciences, University of Birmingham, Birmingham, United Kingdom; 3Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom Abstract Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3’ stem-loop instead of the otherwise universal polyA tail. A metallo b-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. DOI: https://doi.org/10.7554/eLife.39865.001 Introduction During S-phase of the cell cycle, production of the core histone proteins (H2A, H2B, H3, and H4) is *For correspondence: coordinated with DNA replication (Harris et al., 1991; Ewen, 2000). Metazoan mRNAs encoding
[email protected] (NJP); for the ‘replication-dependent’ (RD) core histones lack the normal polyA tail formed by 3’ end hydro-
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