PhD | Understanding the RNA regulatory interactome landscape of radiation response in glioblastoma
Position: Temporary (4 years), fulltime (40 h/week)
Institution: SCK CEN
Location: Mol, Belgium
Application closes at: Mar 24th, 2023 00:00
Glioblastoma (GBM) is the most malignant and frequently occurring type of primary astrocytoma. It accounts for more than 60% of all brain tumors in adults. Despite the availability of traditional treatment options such as surgery, postoperative radiation, and chemotherapy, the median survival of GBM patients remains less than two years. Due to its high aggressiveness, heterogeneity, and easy tolerance to treatment, there is currently no viable treatment for GBM. As a result, it is critical to identify new prognostic markers and treatment options for this devastating cancer.
RNA molecules have regulatory and structural roles in virtually all cellular processes and functions that are executed via RNA-protein interactions. Such interactomes consist of RNA-binding proteins (RBPs) that interact with target RNAs and control all aspects of post-transcriptional gene expression, including RNA splicing and editing, transport and localization, mRNA turnover and translation, as well as miRNA biogenesis. The last decade has seen an increase in studies that have identified RBPs as novel regulators of the DNA damage response (DDR). In response to DNA damage, RBPs play major roles in the regulation of expression of DDR and cell fate genes at multiple transcriptional and post-transcriptional levels. Furthermore, RBPs play roles in various aspects of DNA-based processes beyond transcription that are closely linked to the DDR, such as preventing harmful DNA/RNA hybrids by being directly involved in the maintenance of genome integrity and in DNA repair through interactions with nascent transcripts, ncRNA, damaged DNA, and DNA repair proteins.
Understanding the RNA-protein interactome is thus critical for a better understanding of the regulatory factors and molecular mechanisms that drive radiation response in glioblastoma. As such, targeting RBPs may be a promising treatment strategy for GBM in the future. However, only a few RBPs have been explored in the context of their role in GBM radiation response, and hence the majority of them still remain unidentified. Furthermore, the role of RBPs in controlling DNA damage-dependent RNA metabolism and fate in the context of GBM still needs to be understood.
Here, using large-scale RNA-protein interactome studies, we intend to investigate which pre-mRNAs, mRNAs, and ncRNAs interact with and are regulated by specific RBPs in the presence and absence of DNA damage upon radiation treatment. Relatedly, whether and how RBPs involved in other aspects of RNA metabolism (e.g., alternative polyadenylation, export) that have recently been linked to the DDR will also be investigated. We intend to further study RNA-protein interaction status upon radiation treatment of intratumoral heterogeneous GBM populations. This would help find large-scale post-transcriptional gene regulatory networks and key regulatory events that may cause different responses to DNA damage in different cells.