DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway

EMBO J. 2004 Mar 10;23(5):1133-43. doi: 10.1038/sj.emboj.7600120. Epub 2004 Feb 19.


Activation of the G(1) checkpoint following DNA damage leads to inhibition of cyclin E-Cdk2 and subsequent G(1) arrest in higher eucaryotes. Little, however, is known about the molecular events downstream of cyclin E-Cdk2 inhibition. Here we show that, in addition to the inhibition of DNA synthesis, ionizing radiation induces downregulation of histone mRNA levels in mammalian cells. This downregulation occurs at the level of transcription and requires functional p53 and p21(CIP1/WAF1) proteins. We demonstrate that DNA damage induced by ionizing radiation results in the suppression of phosphorylation of NPAT, an in vivo substrate of cyclin E-Cdk2 kinase and an essential regulator of histone gene transcription, and its dissociation from histone gene clusters in a p53/p21-dependent manner. Inhibition of Cdk2 activity by specific inhibitors in the absence of DNA damage similarly disperses NPAT from histone gene clusters and represses histone gene expression. Our results thus suggest that inhibition of Cdk2 activity following DNA damage results in the downregulation of histone gene transcription through dissociation of NPAT from histone gene clusters.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CDC2-CDC28 Kinases / metabolism
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA Damage / genetics*
  • DNA Replication
  • Down-Regulation* / radiation effects
  • G1 Phase*
  • Histones / genetics*
  • Humans
  • Multigene Family / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Radiation, Ionizing
  • Transcription, Genetic / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histones
  • NPAT protein, human
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2