A non-catalytic function for Rad18 in sustaining glioblastoma proliferation

Abstract

The Rad18 E3 ubiquitin ligase 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 and its downregulation sensitizes glioblastoma cells to DNA damaging agents. Here we show that Rad18 has an essential role in glioblastoma cells proliferation in the absence of external damage, which is independent of its catalytic activity. Rad18 downregulation leads to cell cycle arrest in the G1 phase of the cell cycle in the absence of apparent DNA damage. We also show that Rad18 is essential for glioblastoma stem cells self-renewal and survival, and the growth of tumor orthotropic xenografts in mice. We also show that increased Rad18 expression enhances the growth of transformed cells and induces features of oncogenic transformation. Altogether, these data propose Rad18, a non-essential gene, as a gene essential for GBM proliferation and a key target to sensitize glioblastoma to therapy.