Unravelling the requirement of Rad18 in glioblastoma proliferation
Worldwide Cancer Research
Cancer Research Center of Toulouse
Glioblastoma is the most frequent and aggressive primary brain tumor characterized by a strong resistance to therapy involving treatment with ionizing radiations and alkylating agents. The molecular grounds of this acquired resistance are currently unknown. The identification of novel therapeutic targets constitutes therefore a priority. We and others have recently reported an implication of the Rad18 (E3) ubiquitin ligase in the resistance of glioblastoma to cisplatin and ionizing radiations. Rad18, a critical component of DNA damage bypass, activates translesion synthesis by catalyzing the transfer of an ubiquitin monomer on PCNA, a well-known proliferation-associated antigen. This results in recruitment of translesion synthesis DNA polymerases to allow DNA synthesis through DNA lesions thus facilitating escape of apoptosis and contributing in resistance to therapy. In addition, Rad18 is also implicated in repair of single and double DNA strand breaks as those generated by the radiotherapy. Unexpectedly, by analyzing the phenotypes associated with Rad18 downregulation in glioblastoma, we have observed that Rad18, which is non-essential for life, is essential for the proliferation of glioblastoma cells, and in particular of glioblastoma cancer stem cells (GCSCs), those cells currently strongly implicated in the resistance to the therapy. The aim of this work is to unveil the specific function of Rad18 in the proliferation of GCSCs and to propose Rad18 as novel therapeutic target in the treatment of glioblastoma. This will be achieved thought the identification of the molecular pathway(s) in which Rad18 is implicated through genome-wide analysis of genes and proteins affected by Rad18 expression, as well as by the identification of Rad18 substrates in GCSCs. We will also generate a proof-of-concept for a role of Rad18 in sustaining glioblastoma proiliferation in preclinical models using both wild-type and Rad18 knock-out mice.
2.1 Biological and endogenous factors