Cell-cycle regulation of the DNA topoisomerase IIalpha promoter is mediated by proximal CCAAT boxes: possible involvement of acetylation

Gene. 2000 Mar 7;245(1):49-57. doi: 10.1016/s0378-1119(00)00040-8.


Expression of DNA topoisomerase (topo) IIalpha is cell-cycle-regulated, with its peak in G(2)/M and its lowest level in G(0)/G(1). In agreement with this expression pattern, we have shown that the topo IIalpha gene promoter shows cell-cycle-dependent activity, which is repressed in G(0)/G(1) and activated exclusively in G(2)/M. However, the promoter sequence reveals no canonical CDE/CHR motifs, repressor elements commonly found in promoters of late S/G(2)-activated genes. Here, we show that at least two of the three proximal inverted CCAAT boxes (ICBs) are responsible for the G(2)/M-specific activation of the topo IIalpha promoter. Using antibody supershift experiments, we identify NF-Y as the ICB-binding transcription factor. However, the expression profile and binding capacity of NF-Y were constant during the cell cycle, suggesting a more global mechanism in topo IIalpha promoter regulation. Interestingly, we find that trichostatin A (TSA), a specific histone deacetylase inhibitor, greatly enhances topo IIalpha promoter activity in an ICB-dependent manner. In addition, the effect of TSA is predominant in G(0)/G(1) and less obvious in G(2)/M. Our data, along with the recent findings that NF-Y associates in vivo with histone acetyltransferases (HATs), strongly suggest a mechanism, in which histone deacetylation plays a crucial role in the G(0)/G(1)-specific repression of the topo IIalpha promoter, and NF-Y recruits HATs to the promoter region, thereby stimulating histone acetylation and activating transcription in G(2)/M.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Acetylation
  • Animals
  • Antigens, Neoplasm
  • Base Sequence
  • Binding Sites / genetics
  • CCAAT-Enhancer-Binding Proteins
  • Cell Cycle / physiology*
  • DNA Topoisomerases, Type II* / genetics*
  • DNA Topoisomerases, Type II* / metabolism
  • DNA-Binding Proteins / metabolism
  • G2 Phase / physiology
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids / pharmacology
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism
  • Luciferases / drug effects
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Mitosis / physiology
  • Mutation
  • Oligonucleotides / genetics
  • Oligonucleotides / metabolism
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Antigens, Neoplasm
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Isoenzymes
  • Oligonucleotides
  • Recombinant Fusion Proteins
  • trichostatin A
  • Luciferases
  • DNA Topoisomerases, Type II