We propose that a deficiency in the DNA non-homologous end-joining (D-NHEJ) pathway due to the downregulation of LIG4 could lead to a synthetic lethal interaction with the deficiency in the backup non-homologous end-joining (B-NHEJ) pathway induced by PARP inhibitors (PARPi) in glioblastoma cells that experience DNA damage from temozolomide (TMZ) treatment. The gene discussed is LIG4; the disease is glioblastoma.