Molecular insights into DNA damage response plasticity in glioma stem cells

High-grade gliomas frequently recur after radiotherapy and temozolomide because tumor cells can adapt to sustained DNA damage. This Review discusses how glioma stem cells contribute to this resistance by rewiring the DNA damage response rather than simply increasing DNA repair efficiency. We examine how checkpoint signaling, replication stress tolerance, DNA repair pathway choice, chromatin and RNA-based regulation, translational control, metabolism and microenvironmental cues cooperate to preserve survival under genotoxic stress. By integrating these mechanisms, we define DNA damage response plasticity as an adaptive network that supports tumor persistence and recurrence, while exposing vulnerabilities that may guide more effective therapeutic strategies.