Lana Dokic

Background: Radiotherapy (RT) is a major component of cancer treatment and is used in approximately 50-60% of patients with malignancy.¹ The therapeutic efficacy of RT depends on induction of DNA double-strand breaks (DSBs), which activate DNA damage response (DDR) pathways that regulate DNA repair, apoptosis, cell cycle arrest, and genomic stability.¹ TP53 is a critical tumor suppressor gene that coordinates cellular responses to radiation-induced DNA damage.² TP53 mutations occur in nearly half of all human cancers and are associated with genomic instability, aggressive tumor behavior, and poor clinical outcomes.² Despite the established role of TP53 in DDR regulation, responses to radiotherapy remain highly variable across tumor types and patients, suggesting that additional molecular and functional mechanisms influence radiosensitivity and radioresistance.³

Objective: This review examined how TP53 dysfunction alters DNA damage response pathways and influences radiosensitivity, with emphasis on radiotherapy fractionation sensitivity, DNA repair pathway selection, and therapeutic vulnerabilities associated with TP53 mutant tumors.

Search Methods: A literature review was conducted using the PubMed database for studies published between 2017 and 2025. Search terms included “TP53,” “p53,” “DNA damage response,” “radiotherapy,” “radioresistance,” “ATM inhibition,”and “homologous recombination.”

Results: Anbalagan demonstrated that functional p53 signaling promotes split dose recovery through coordination of G1/S checkpoint activation and DNA repair between radiation fractions, whereas TP53 deficient cells lose this recovery capacity and demonstrate impaired survival following fractionated radiation. This is clinically significant because fractionated radiotherapy relies on this recovery process to spare normal tissue while targeting tumor cells.⁴ Issing further demonstrated substantial variability in radiation response among patient derived tumor organoids that did not consistently correlate with TP53 mutation status alone, suggesting that p53 alone is insufficient to predict radiotherapy response.⁵ Chen found that TP53 mutant glioblastoma cells rely more heavily on homologous recombination (HR) and ATM signaling for DNA repair following radiation exposure.⁶ Treatment with the ATM inhibitor AZD1390 selectively increased radiosensitivity in TP53 mutant tumors by impairing DNA repair and increasing tumor cell death, while TP53 wild type tumors showed minimal response, suggesting that TP53 mutation status may help identify patients who could benefit from ATM inhibitor radiotherapy.⁶ Fagherazzi found that specific TP53 mutations impair recruitment of 53BP1 to DNA double strand break sites, disrupting nonhomologous end joining (NHEJ) and shifting repair toward homologous recombination (HR).⁷ TP53 mutant cells demonstrated increased genomic instability and enhanced survival following radiation exposure, supporting a radioresistant phenotype.⁷ These findings suggest that specific TP53 mutations alter DNA repair pathway selection and may contribute to variability in radiotherapy response across tumors.⁷

Conclusion: TP53 dysfunction significantly alters cellular response to ionizing radiation by disrupting checkpoint regulation, modifying DNA repair pathway selection, and promoting genomic instability and radioresistance. While TP53 mutation status alone is insufficient to fully predict treatment response, integration of molecular profiling with functional assays such as patient derived organoid testing may improve individualized radiotherapy strategies. Emerging DDR targeted therapies, including ATM inhibition, represent promising radiosensitization approaches for TP53 mutant tumors. Continued investigation of TP53 mediated DDR pathways may support the transition from standardized radiotherapy approaches toward biologically guided precision oncology.

Works Cited

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