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

S.M. Nicol, S.E. Bray, H. Derek Black, S.A. Lorimore, E.G. Wright, D.P. Lane, D.W. Meek, P.J. Coates, F.V. Fuller-Pace (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    38 Citations (Scopus)

    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 , 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 ?-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.Oncogene advance online publication, 17 September 2012; doi:10.1038/onc.2012.426.
    Original languageEnglish
    Pages (from-to)3461-3469
    Number of pages9
    JournalOncogene
    Volume32
    Issue number29
    DOIs
    Publication statusPublished - 18 Jul 2013

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    DEAD-box RNA Helicases
    Cell Cycle Checkpoints
    DNA Damage
    Apoptosis
    cdc Genes
    RNA Polymerase II
    Biological Factors
    Oncogenes
    Knockout Mice
    Transcriptional Activation
    Publications
    Bone Marrow
    Growth
    Genes
    Neoplasms

    Cite this

    Nicol, S.M. ; Bray, S.E. ; Derek Black, H. ; Lorimore, S.A. ; Wright, E.G. ; Lane, D.P. ; Meek, D.W. ; Coates, P.J. ; Fuller-Pace, F.V. / The RNA helicase p68 (DDX5) is selectively required for the induction of p53-dependent p21 expression and cell-cycle arrest after DNA damage. In: Oncogene. 2013 ; Vol. 32, No. 29. pp. 3461-3469.
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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 p21 , 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 ?-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.Oncogene advance online publication, 17 September 2012; doi:10.1038/onc.2012.426.",
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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. / Nicol, S.M.; Bray, S.E.; Derek Black, H.; Lorimore, S.A.; Wright, E.G.; Lane, D.P.; Meek, D.W.; Coates, P.J.; Fuller-Pace, F.V. (Lead / Corresponding author).

    In: Oncogene, Vol. 32, No. 29, 18.07.2013, p. 3461-3469.

    Research output: Contribution to journalArticle

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    AU - Bray, S.E.

    AU - Derek Black, H.

    AU - Lorimore, S.A.

    AU - Wright, E.G.

    AU - Lane, D.P.

    AU - Meek, D.W.

    AU - Coates, P.J.

    AU - Fuller-Pace, F.V.

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