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The RNA helicase p68 (DDX5) is selectively required for the induction of p53-dependent p21 expression and cell-cycle arrest after DNA damage

Oncogene volume 32, pages 3461–3469 (2013)Cite this article

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Abstract

The RNA helicase p68 (DDX5) is an established co-activator of the p53 tumour suppressor that itself has a pivotal role in orchestrating the cellular response to DNA damage. Although several factors influence the biological outcome of p53 activation, the mechanisms governing the choice between cell-cycle arrest and apoptosis remain to be elucidated. In the present study, we show that, while p68 is critical for p53-mediated transactivation of the cell-cycle arrest gene p21WAF1/CIP1, it is dispensable for induction of several pro-apoptotic genes in response to DNA damage. Moreover, p68 depletion results in a striking inhibition of recruitment of p53 and RNA Pol II to the p21 promoter but not to the Bax or PUMA promoters, providing an explanation for the selective effect on p21 induction. Importantly, these findings are mirrored in a novel inducible p68 knockout mouse model in which p68 depletion results in a selective inhibition of p21 induction in several tissues. Moreover, in the bone marrow, p68 depletion results in an increased sensitivity to γ-irradiation, consistent with an increased level of apoptosis. These data highlight a novel function of p68 as a modulator of the decision between p53-mediated growth arrest and apoptosis in vitro and in vivo.

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Acknowledgements

We thank Colin Henderson for helpful discussions. This work was supported by grants from Cancer Research UK (C8745/A11216) and the Association for International Cancer Research (06–613).

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Authors and Affiliations

  1. Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK

    S M Nicol, S A Lorimore, E G Wright, D W Meek & F V Fuller-Pace

  2. Tayside Tissue Bank, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK

    S E Bray & P J Coates

  3. Medical School Resource Unit, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK

    H Derek Black

  4. p53 Lab, Immunos, A*Star, Singapore, Singapore

    D P Lane

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  1. S M Nicol
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Correspondence to F V Fuller-Pace.

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Nicol, S., Bray, S., Derek Black, H. et al. The RNA helicase p68 (DDX5) is selectively required for the induction of p53-dependent p21 expression and cell-cycle arrest after DNA damage. Oncogene 32, 3461–3469 (2013). https://doi.org/10.1038/onc.2012.426

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