Human histone pre-mRNA assembles histone or canonical mRNA-processing complexes by overlapping 3'-end sequence elements

Nucleic Acids Res. 2022 Nov 28;50(21):12425-12443. doi: 10.1093/nar/gkac878.


Human pre-mRNA processing relies on multi-subunit macromolecular complexes, which recognize specific RNA sequence elements essential for assembly and activity. Canonical pre-mRNA processing proceeds via the recognition of a polyadenylation signal (PAS) and a downstream sequence element (DSE), and produces polyadenylated mature mRNAs, while replication-dependent (RD) histone pre-mRNA processing requires association with a stem-loop (SL) motif and a histone downstream element (HDE), and produces cleaved but non-polyadenylated mature mRNAs. H2AC18 mRNA, a specific H2A RD histone pre-mRNA, can be processed to give either a non-polyadenylated mRNA, ending at the histone SL, or a polyadenylated mRNA. Here, we reveal how H2AC18 captures the two human pre-mRNA processing complexes in a mutually exclusive mode by overlapping a canonical PAS (AAUAAA) sequence element with a HDE. Disruption of the PAS sequence on H2AC18 pre-mRNA prevents recruitment of the canonical complex in vitro, without affecting the histone machinery. This shows how the relative position of cis-acting elements in histone pre-mRNAs allows the selective recruitment of distinct human pre-mRNA complexes, thereby expanding the capability to regulate 3' processing and polyadenylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Histones* / genetics
  • Histones* / metabolism
  • Humans
  • Polyadenylation
  • RNA Precursors* / genetics
  • RNA Precursors* / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • mRNA Cleavage and Polyadenylation Factors / genetics


  • RNA Precursors
  • Histones
  • mRNA Cleavage and Polyadenylation Factors
  • RNA, Messenger