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HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition.

Genome replication in eukaryotic cells necessitates the stringent coupling of histone biosynthesis with the onset of DNA replication at the G1/S phase transition. A fundamental question is the mechanism that links the restriction (R) point late in G1 with histone gene expression at the onset of S phase. Here we demonstrate that HiNF-P, a transcriptional regulator of replication-dependent histone H4 genes, interacts directly with p220(NPAT), a substrate of cyclin E/CDK2, to coactivate histone genes during S phase. HiNF-P and p220 are targeted to, and colocalize at, subnuclear foci (Cajal bodies) in a cell cycle-dependent manner. Genetic or biochemical disruption of the HiNF-P/p220 interaction compromises histone H4 gene activation at the G1/S phase transition and impedes cell cycle progression. Our results show that HiNF-P and p220 form a critical regulatory module that directly links histone H4 gene expression at the G1/S phase transition to the cyclin E/CDK2 signaling pathway at the R point.

Pubmed ID: 15988025


  • Miele A
  • Braastad CD
  • Holmes WF
  • Mitra P
  • Medina R
  • Xie R
  • Zaidi SK
  • Ye X
  • Wei Y
  • Harper JW
  • van Wijnen AJ
  • Stein JL
  • Stein GS


Molecular and cellular biology

Publication Data

July 30, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA82834
  • Agency: NIGMS NIH HHS, Id: GM32010
  • Agency: NIGMS NIH HHS, Id: GM54137
  • Agency: NIDDK NIH HHS, Id: P30 DK32520

Mesh Terms

  • Amino Acid Motifs
  • Animals
  • CDC2-CDC28 Kinases
  • Cell Cycle Proteins
  • Cell Nucleus
  • Chromatin
  • Cyclin E
  • Cyclin-Dependent Kinase 2
  • G1 Phase
  • Gene Expression Regulation
  • Histones
  • Humans
  • Mutation
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Protein Interaction Mapping
  • Repressor Proteins
  • S Phase
  • Transcription, Genetic
  • Transcriptional Activation