Biosynthesis of histone messenger RNA employs a specific 3' end endonuclease

Elife. 2018 Dec 3:7:e39865. doi: 10.7554/eLife.39865.

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 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.

Keywords: MBL domain containing protein 1; S-phase; cell biology; chromosomes; endoribonuclease; gene expression; histone pre-mRNA 3' end processing; human; metallo β-lactamase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Endoribonucleases / chemistry*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Histones / biosynthesis*
  • Histones / genetics
  • Humans
  • Hydrolases
  • Kinetics
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • RNA, Messenger / biosynthesis*
  • RNA, Messenger / genetics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • S Phase Cell Cycle Checkpoints
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • beta-Lactamases / chemistry
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Histones
  • RNA, Messenger
  • Recombinant Proteins
  • Hydrolases
  • Endoribonucleases
  • MBLAC1 protein, human
  • RNase Z
  • LACTB2 protein, human
  • beta-Lactamases