CstF64: cell cycle regulation and functional role in 3' end processing of replication-dependent histone mRNAs

Mol Cell Biol. 2014 Dec 1;34(23):4272-84. doi: 10.1128/MCB.00791-14. Epub 2014 Sep 29.


The 3' end processing of animal replication-dependent histone mRNAs is activated during G1/S-phase transition. The processing site is recognized by stem-loop binding protein and the U7 snRNP, but cleavage additionally requires a heat-labile factor (HLF), composed of cleavage/polyadenylation specificity factor, symplekin, and cleavage stimulation factor 64 (CstF64). Although HLF has been shown to be cell cycle regulated, the mechanism of this regulation is unknown. Here we show that levels of CstF64 increase toward the S phase and its depletion affects histone RNA processing, S-phase progression, and cell proliferation. Moreover, analyses of the interactions between CstF64, symplekin, and the U7 snRNP-associated proteins FLASH and Lsm11 indicate that CstF64 is important for recruiting HLF to histone precursor mRNA (pre-mRNA)-resident proteins. Thus, CstF64 is central to the function of HLF and appears to be at least partly responsible for its cell cycle regulation. Additionally, we show that misprocessed histone transcripts generated upon CstF64 depletion mainly accumulate in the nucleus, where they are targets of the exosome machinery, while a small cytoplasmic fraction is partly associated with polysomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Calcium-Binding Proteins / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Cleavage And Polyadenylation Specificity Factor / genetics*
  • Cleavage Stimulation Factor
  • HEK293 Cells
  • HeLa Cells
  • Histones / genetics*
  • Humans
  • Nuclear Proteins / genetics*
  • RNA 3' End Processing / genetics*
  • RNA Precursors / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*
  • Ribonucleoprotein, U7 Small Nuclear / genetics
  • S Phase / genetics


  • Apoptosis Regulatory Proteins
  • CASP8AP2 protein, human
  • CSTF2T protein, human
  • Calcium-Binding Proteins
  • Cleavage And Polyadenylation Specificity Factor
  • Cleavage Stimulation Factor
  • Histones
  • Lsm11 protein, human
  • Nuclear Proteins
  • RNA Precursors
  • RNA-Binding Proteins
  • Ribonucleoprotein, U7 Small Nuclear
  • SYMPK protein, human