title: 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.
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Nicol
authors.forename: S E
authors.initials: SE
authors.lastname: Bray
authors.forename: H Derek
authors.initials: HD
authors.lastname: Black
authors.forename: S A
authors.initials: SA
authors.lastname: Lorimore
authors.forename: E G
authors.initials: EG
authors.lastname: Wright
authors.forename: D P
authors.initials: DP
authors.lastname: Lane
authors.forename: D W
authors.initials: DW
authors.lastname: Meek
authors.forename: P J
authors.initials: PJ
authors.lastname: Coates
authors.forename: F V
authors.initials: FV
authors.lastname: Fuller-Pace
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases