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Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation

Oncogene volume 19, pages 2714–2720 (2000)Cite this article

Abstract

The apoptotic response and the level of expression of p53 and of three genes transcriptionally activated by p53 (Mdm2, p21 and bax) were investigated in UV-sensitive cells from patients with xeroderma pigmentosum (XP) or Cockayne syndome (CS). These disorders are due to different genetic defects affecting transcription-coupled repair (TCR) and/or global genome repair (GGR), the nucleotide excision repair subpathways which remove UV-induced lesions from the transcribed strand of active genes or from the rest of the genome, respectively. After 20 J/m2 UV light, normal and GGR-defective XP-C fibroblasts showed rapid increase in p53, late induction of Mdm2 and no evidence of apoptosis even 96 h after irradiation. In contrast, in XP-A (defective in GGR and TCR), CS-A and CS-B (defective only in TCR) fibroblasts, the p53 increase was not followed by Mdm2 induction and the persistence of high levels of p53, due to the lack of its degradation by Mdm2, was associated with the appearance of apoptosis. Besides indicating that the persistence of DNA damage in the transcribed strand of active genes leads to apoptosis, these findings provide the first evidence that the lack of activation of Mdm2 plays a key role in the cascade of events leading to apoptosis.

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Acknowledgements

The authors thank Dr AI Scovassi for insightful discussions. This work was supported in part by Telethon grant E.550 to M Stefanini and by AIRC grants to M Stefanini and M D'Incalci.

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Authors and Affiliations

  1. Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, Milano, 20157, Italy

    Grazia Conforti & Maurizio D'Incalci

  2. Istituto di Genetica Biochimica ed Evoluzionistica CNR, Via Abbiategrasso, 207, Pavia, 27100, Italy

    Tiziana Nardo & Miria Stefanini

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  1. Grazia Conforti
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  2. Tiziana Nardo
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  3. Maurizio D'Incalci
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  4. Miria Stefanini
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Conforti, G., Nardo, T., D'Incalci, M. et al. Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation. Oncogene 19, 2714–2720 (2000). https://doi.org/10.1038/sj.onc.1203583

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