Reduced DDB2 Expression Is Associated with Temozolomide Resistance in Glioblastoma Cells

Glioblastoma (GBM) remains one of the most lethal primary brain tumours, and resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, represents a major obstacle to effective treatment. Although O⁶-methylguanine-DNA methyltransferase (MGMT) is a well-established determinant of TMZ response, MGMT status alone does not fully explain the heterogeneity of treatment outcomes, suggesting the involvement of additional DNA damage response mechanisms. Here, we investigated the contribution of different DNA repair pathways to TMZ sensitivity in a panel of GBM cell lines displaying distinct TMZ response profiles. Expression analysis of 84 DNA repair genes identified damage-specific DNA binding protein 2 (DDB2) as the only one consistently associated with TMZ sensitivity. We found that DDB2 expression was significantly reduced in TMZ-resistant cell lines and selectively induced following TMZ exposure in TMZ-sensitive cells. Proteomic profiling of representative sensitive and resistant cell models further revealed distinct responses to TMZ and identified enrichment of p53-associated DNA damage response pathways in sensitive cells, including altered expression of DDB2 and other canonical p53-regulated proteins. Importantly, siRNA-mediated depletion of DDB2 in the TMZ-sensitive A172 GBM cell line significantly reduced TMZ sensitivity. These findings provide functional evidence that DDB2 contributes to the cellular response to TMZ and extend the established roles of DDB2 in DNA repair and cancer biology to TMZ responsiveness in GBM.