PROJECT SUMMARY Glioblastoma (GBM) is an aggressive type of brain cancer that arises de novo and is therapy resistant. A key contributor to poor outcomes in GBM is a subpopulation of cells called glioma stem-like cells (GSCs) that evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype transition. TAZ driven cell fate change is accompanied by aggressive behavior such as increased grade, necrosis and radio-resistance. Silencing YAP/TAZ ablates tumor growth by activating neurogenic programs, thus making these proteins attractive therapeutic targets. Although the oncogenic functions of YAP/TAZ are well established in GBM, the exact molecular mechanisms underlying cell fate transition and their contribution to therapy resistance are not fully understood. We have now accumulated substantial evidence to pinpoint a direct role for YAP/TAZ in DNA damage response pathway, a network of proteins that sense and repair DNA lesions in response to ionizing radiation (IR) treatments. YAP/TAZ also cause by enhancer reprogramming and recruitment of distinct molecular complexes in proneural and mesenchymal gene enhancers, which offers protection of DNA damage vulnerable regions of the genome. In this proposal, we will deeply investigate the molecular mechanisms underlying YAP/TAZ driven control of neurogenic programs and radio-resistance using both conventional and state-of-the-art molecular, cellular and biochemical approaches. Importantly, we will evaluate the therapeutic benefit of novel pharmacological inhibitors of the YAP/TAZ in combination with IR using pre-clinical models of GBM. Successful completion of these studies will not only unravel the mechanistic underpinnings behind neuronal differentiation and DNA damage repair in GBM, but also inform the development of next generation of clinical trials for GBM.