A non-catalytic function for RAD18 in sustaining glioblastoma proliferation

The RAD18 (E3) ubiquitin ligase, a key DNA damage tolerance regulator that also functions in DNA double-strand break repair, is overexpressed in the brain cancer glioblastoma. Here, we show that RAD18 promotes glioblastoma cell proliferation in the absence of exogenous damage, independently of its catalytic activity. RAD18 downregulation arrests glioblastoma cells in the G1 phase of the cell cycle, leading to senescence onset, with no apparent increase in DNA damage. We also show that RAD18 sustains glioblastoma stem cells' self-renewal and the growth of tumor orthotropic xenografts in mice. Further, we show that increased RAD18 expression enhances the growth of non-transformed cells and induces the features of oncogenic transformation. Mechanistically, RAD18 interacts and negatively regulates the NF2 tumor suppressor through its SAP domain, thereby facilitating stabilization and nuclear retention of the YAP1 transcription factor. Altogether, these data propose RAD18 as a key target to sensitize glioblastoma to therapy.