DNA Damage Response Mechanisms in Glioblastoma

Glioblastoma multiforme is characterised by rampant genomic instability and resistance to conventional chemoradiation, driven in part by a hyperactive DNA damage response (DDR). In normal cells, damage sensors such as ATR and ATM kinases detect lesions and orchestrate cell cycle arrest, repair and, if necessary, apoptosis. In glioblastoma, these pathways are frequently hijacked: enhanced base excision repair and mismatch repair neutralise alkylation damage induced by temozolomide, while overexpression of key factors such as MGMT, PARP and RRM2 accelerates single- and double-strand break repair. Aberrant checkpoint activation mediated by Chk1 and Chk2 promotes tumour cell survival under genotoxic stress. Simultaneously, alterations in homologous recombination and non-homologous end joining confer resistance to irradiation. Emerging evidence reveals that metabolic enzymes intersect with DDR signalling, modulating nucleoside pools and redox balance to fuel DNA repair. Collectively, a complex network of sensing, signalling and repair processes underpins therapeutic resistance in glioblastoma, making DDR components both mechanistic drivers of malignancy and promising targets for novel combinatorial treatments.

Research from Nature Portfolio

Recent studies have delineated a dual role for standard chemotherapy in orchestrating DNA repair in glioblastoma. One investigation revealed that temozolomide metabolites activate AMPK through HPRT1-dependent conversion of 5-aminoimidazole-4-carboxamide to AICAR, leading to phosphorylation and activation of ribonucleotide reductase; this metabolic rerouting enhances dNTP synthesis and facilitates repair of chemotherapy-induced lesions, thereby promoting chemoresistance. Pharmacological inhibition of HPRT1 sensitises tumour cells to temozolomide in vivo, suggesting an adjunct strategy to impede repair. Another foundational work identified a non-canonical tumour-promoting function of BRCA1 in glioblastoma, wherein BRCA1 acts as a transcriptional co-activator of RRM2, safeguarding cells from replication stress and cell death. Disruption of this axis elevates DNA damage, diminishes tumourigenicity and unveils synergy with PARP blockade, highlighting the BRCA1-RRM2 pathway as a novel therapeutic liability.

DNA Damage Response Mechanisms in Glioblastoma publication trend

The graph below shows the total number of articles in dna damage response mechanisms in glioblastoma across all publications each year (not limited to Nature Index journals).

Technical terms

DNA damage response (DDR): A coordinated network of sensors, transducers and effectors that detect DNA lesions, arrest the cell cycle and mediate repair or apoptosis.

Temozolomide (TMZ): An alkylating chemotherapeutic agent used as standard treatment for glioblastoma, inducing methylation lesions in DNA.

Poly(ADP-ribose) polymerase (PARP): An enzyme family essential for single-strand break repair via base excision repair; PARP inhibitors trap the enzyme on DNA, preventing repair.

Ataxia telangiectasia and Rad3 related (ATR): A protein kinase activated by single-strand DNA regions that coordinates cell cycle checkpoints and repair under replication stress.

Ribonucleotide reductase (RNR): An enzyme complex that catalyses deoxynucleotide synthesis, providing dNTPs required for DNA replication and repair.

References

1. Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas. Nature Communications (2023).
2. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. Nature Communications (2016).
3. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis. Neuro-Oncology (2023).
4. Functionally-instructed modifiers of response to ATR inhibition in experimental glioma. Journal of Experimental & Clinical Cancer Research (2024).
5. Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth. Cell Death & Disease (2023).