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  • The EMBO Journal (2004) 23, 1133 - 1143
  • doi:10.1038/sj.emboj.7600120

Published online: 19 February 2004

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

Chuan Su1,a, Guang Gao1, Sandra Schneider1, Christopher Helt2, Carsten Weiss1, Michael A O'Reilly3, Dirk Bohmann1 and Jiyong Zhao1

  1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
  2. Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA
  3. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA

Correspondence to:

Jiyong Zhao, Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA. Tel.: +1 585 273 1453; Fax: +1 585 273 1450; E-mail: jiyong_zhao@urmc.rochester.edu

aPresent address: Department of Parasitology, Wanjing Medical University, Wanjing, Jiangsu 210029, PR China

Received 25 June 2003; Accepted 8 December 2003

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.

  • Keywords:

    • checkpoints,
    • cyclin E–Cdk2,
    • DNA damage,
    • histone gene expression,
    • NPAT