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Molecular and Cellular Biology, April 2000, p. 2358-2366, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G2/M Arrest in Human Cells

Christophe Badie, Jane E. Itzhaki,dagger Matthew J. Sullivan, Adam J. Carpenter, and Andrew C. G. Porter*

Gene Targeting Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom

Received 11 August 1999/Returned for modification 28 September 1999/Accepted 29 December 1999

Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G2/M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G2 arrest appears to involve additional mechanisms. We describe here the prolonged (>6 day) downregulation of CDK1 protein and mRNA levels following DNA damage in human cells. This silencing of gene expression is observed in primary human fibroblasts and in two cell lines with functional p53 but not in HeLa cells, where p53 is inactive. Silencing is accompanied by the accumulation of cells in G2, when CDK1 expression is normally maximal. The response is impaired by mutations in cis-acting elements (CDE and CHR) in the CDK1 promoter, indicating that silencing occurs at the transcriptional level. These elements have previously been implicated in the repression of transcription during G1 that is normally lifted as cells progress into S and G2. Interestingly, we find that other genes, including those for CDC25C, cyclin A2, cyclin B1, CENP-A, and topoisomerase IIalpha , that are normally expressed preferentially in G2 and whose promoter regions include putative CDE and CHR elements are also downregulated in response to DNA damage. These data, together with those of other groups, support the existence of a p53-dependent, DNA damage-activated pathway leading to CHR- and CDE-mediated transcriptional repression of various G2-specific genes. This pathway may be required for sustained periods of G2 arrest following DNA damage.

* Corresponding author. Mailing address: Gene Targeting Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. Phone: (44)-181-383-8276. Fax: (44)-181-383-8303. E-mail: andy.porter{at}csc.mrc.ac.uk.

dagger Present address: The Wellcome Trust, London NW1 2BE, United Kingdom.

Molecular and Cellular Biology, April 2000, p. 2358-2366, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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