National University of Singapore
TO INVESTIGATE THE ROLE OF RNF8 IN REGULATING MITOTIC PROGRESSION IN GLIOMAS
Abstract
dc:description.abstractGlioblastoma (GBM) is a lethal brain tumour that is driven by glioma stem cells (GSCs). The E3 ubiquitin ligase RNF8, an established DNA damage response factor, has been implicated in spindle assembly checkpoint (SAC) but its exact role remains unknown. Using RNF8 proximity proteomics, we find that RNF8 interacts with MAD2 and CAMK2D via its RING and FHA domains respectively to activate the SAC response. The physiological relevance of our mechanistic findings is illustrated in GSCs whereby the overexpression of wild-type RNF8, but not the FHA or RING mutant, blocks GSC mitotic progression and augments genome instability. Indeed, low RNF8 expression portends poor patient prognosis in glioma patients. Importantly, our mechanistic findings led to the rational combination of PLK1 and HSP90 inhibitors that elicit an additive effect in reducing GSC proliferation and stemness. Thus, our study has unveiled a novel mechanism of RNF8 in SAC regulation, with relevance to gliomas.
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
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- CHUAH YOU HENG