The rna helicase p68 (ddx5) is selectively required for the induction of p53-dependent p21 expression and cell-cycle arrest after dna damage

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 _p21__WAF1/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._ Access through your

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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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Tayside Tissue Bank, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK S E Bray & P J Coates * Medical

School Resource Unit, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK H Derek Black * p53 Lab, Immunos, A*Star, Singapore, Singapore D P Lane Authors * S M Nicol

View author publications You can also search for this author inPubMed Google Scholar * S E Bray View author publications You can also search for this author inPubMed Google Scholar * H Derek

Black View author publications You can also search for this author inPubMed Google Scholar * S A Lorimore View author publications You can also search for this author inPubMed Google

Scholar * E G Wright View author publications You can also search for this author inPubMed Google Scholar * D P Lane View author publications You can also search for this author inPubMed 

Google Scholar * D W Meek View author publications You can also search for this author inPubMed Google Scholar * P J Coates View author publications You can also search for this author

inPubMed Google Scholar * F V Fuller-Pace View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to F V Fuller-Pace. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website SUPPLEMENTARY

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 16 April 2012 *

Revised: 06 July 2012 * Accepted: 31 July 2012 * Published: 17 September 2012 * Issue Date: 18 July 2013 * DOI: https://doi.org/10.1038/onc.2012.426 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * p68 (DDX5) RNA helicase * p53 * DNA damage * cell-cycle arrest * apoptosis