A non-catalytic function for Rad18 in sustaining glioblastoma proliferation

The Rad18 E3 ubiquitin ligase, a non-essential gene, is a key regulator of DNA damage tolerance that also functions in repair of DNA double strand breaks. Rad18 is overexpressed in the aggressive brain cancer glioblastoma (GBM) and its downregulation sensitizes glioblastoma cells to DNA damaging agents. Here we show that Rad18 has an essential role in GBM cells proliferation in the absence of external damage, surprisingly independent of its catalytic activity. Rad18 downregulation leads to cell cycle arrest in the G1 phase in the absence of apparent DNA damage. We also show that Rad18 sustains GBM stem cells self-renewal and survival, as well as the growth of tumor orthotropic xenografts in mice. We also show that increased Rad18 expression enhances the growth of non-transformed cells and induces features of oncogenic transformation. Mechanistically, we show that Rad18 downregulation negatively regulates the Hippo pathway by interfering with the nuclear retention of the YAP1 transcription factor. Altogether, these data show that Rad18 has an essential, non-catalytic function, in GBM proliferation, and propose Rad18 as a key target to sensitize GBM to therapy.