p68 (DDX5) is a prototypic member of the DEAD box family of RNA helicases that can unwind RNA in a context-selective and ATP-dependent manner. p68 is a multi-functional protein known to be involved in several cellular processes requiring manipulation of RNA structures, including transcription and processing of pre-mRNA, rRNA, and miRNA.
We have previously shown that p68 is a potent co-activator of the p53 tumour suppressor, a tightly regulated transcription factor that plays a pivotal role in orchestrating the cellular response to tumorigenic agents such as activated oncogenes or 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. We have demonstrated that p68 is selectively required for p53-mediated transactivation of the cell cycle arrest gene p21WAF1 in response to DNA damage in vitro and in vivo. Our data highlight a novel function of p68 as a selective regulator of the p53 DNA damage response and demonstrate that it can modulate the decision between cell cycle arrest and apoptosis in a context- dependent manner.
The prroposed project will employ a range of molecular and cell biology techniques to explore the mechanisms by which p68 modulates the p53 response to chemotherapy and radiotherapy. This is particularly interesting since p68 is aberrantly expressed and modified in a wide range of cancers and could therefore modulate p53-dependent tissue responses to radiotherapy or chemotherapy by determining whether cells survive or die. A better understanding of the role of p68 in determining the outcome of p53 activation could be important in the development of better therapeutic strategies for cancer treatment, or choice of treatment depending on p53 and p68 status, that strike the correct balance between cell-cycle arrest/DNA repair and apoptosis to achieve the optimal therapeutic effect and minimize deleterious side effects.
Nicol SM, Bray SE, Black HD, Lorimore SA, Wright EG, Lane DP, Meek DW, Coates PJ & Fuller-Pace FV (2013) 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.
Bates GJ, Nicol SM, Wilson BJ, Jacobs, A-MF, Bourdon J-C, Wardrop J, Gregory DJ, Lane DP, Perkins ND & Fuller-Pace FV. (2005) The DEAD box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor. EMBO J. 24: 543-553.