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

Chuan Su, Guang Gao, Sandra Schneider, Christopher Helt, Carsten Weiss, Michael A. O'Reilly, Dirk Bohmann, Jiyong Zhao

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


Activation of the G1 checkpoint following DNA damage leads to inhibition of cyclin E-Cdk2 and subsequent G1 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 p21CIP1/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.

Original languageEnglish
Pages (from-to)1133-1143
Number of pages11
JournalEMBO Journal
Issue number5
StatePublished - 10 Mar 2004
Externally publishedYes


  • Checkpoints
  • Cyclin E-Cdk2
  • DNA damage
  • Histone gene expression
  • NPAT


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