Further investigation of the E3 ligase cIAP2, and the radiosensitising effects of Smac mimetics

Our laboratory is interested in the DNA damage signalling protein MRE11, and we recently showed that MRE11 was downregulated in response to histone deacetylase inhibition by panobinostat, and that downregulation of MRE11 is associated with increased radiosensitivity. Furthermore, this downregulation is in part mediated by the E3 ligase cIAP2 (encoded by the BIRC3 gene).We are trying to find radiosensitising agents which, when added to radiotherapy, will improve patient survival without increasing the side effects of radiotherapy. This project will investigate a group of agents called small molecule Smac mimetics as putative radiosensitisers, as these can activate cIAP2 activity, including their underlying mechanism of action which we hypothesise may involve MRE11 downregulation.