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.
Highlights
During S-phase of the cell cycle, production of the core histone proteins (H2A, H2B, H3, and H4) is coordinated with DNA replication (Harris et al, 1991; Ewen, 2000)
Specific factors involved in RD histone pre-mRNA maturation are the stem loop binding protein (SLBP), the FLICE-associated huge protein (FLASH), and the U7 small nuclear ribonucleoprotein (U7snRNP) that binds to a histone downstream element (HDE) (Dominski et al, 2005; Kolev et al, 2008; Sullivan et al, 2009b)
Assays with isolated recombinant MBL domain containing protein 1 (MBLAC1) reveal it is selective for hydrolytic cleavage at the biologically relevant CA dinucleotides present 5 and 7 nucleotides downstream of the stem-loop sequence in replication-dependent pre-mRNA
Summary
During S-phase of the cell cycle, production of the core histone proteins (H2A, H2B, H3, and H4) is coordinated with DNA replication (Harris et al, 1991; Ewen, 2000). Metazoan mRNAs encoding for the ‘replication-dependent’ (RD) core histones lack the normal polyA tail formed by 3’ end hydrolysis of pre-mRNA followed by polyadenylation (Proudfoot, 2011). Instead, they undergo endonucleolytic cleavage at the 3’ side of an RNA hairpin (stem loop) producing mRNA with a 3 ́stem loop (SL), which is exported from the nucleus for use in translation (Marzluff et al, 2008; Marzluff and Koreski, 2017). In Drosophila melanogaster and humans, misprocessed RD histone pre-mRNA has been observed to undergo polyadenylation involving utilization of a secondary polyadenylation signal sequence located
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