DNA Repair Mechanisms in Cancer Therapeutics

Genomic stability relies on coordinated DNA repair pathways that correct lesions ranging from single-base modifications to complex double-strand breaks (DSBs). In cancer therapeutics, these pathways represent both obstacles and opportunities: tumour cells often harbour intrinsic defects in one repair mechanism and compensate by upregulating alternative routes, creating vulnerabilities that can be exploited via synthetic lethality. The two principal DSB repair programmes—homologous recombination (HR) and non-homologous end joining (NHEJ)—operate alongside base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) to preserve DNA integrity. Targeted agents such as PARP inhibitors, DNA-PKcs inhibitors and small molecules against ATM/ATR kinases obstruct damage resolution, sensitising tumours to chemotherapy and radiotherapy. Advances in biomarker selection, combination strategies and nanocarrier delivery systems are broadening the precision of repair-targeted interventions, seeking to maximise anti-tumour activity while limiting harm to normal tissues.

Research from Nature Portfolio

Recent studies have demonstrated that tissue-specific modulation of p53 activity governs repair pathway choice and cellular outcomes in models of DNA repair deficiency, revealing differential organ reliance on particular repair axes. Another investigation introduced a highly selective inhibitor of DNA-PKcs that, by blocking NHEJ, markedly enhanced the efficacy of radiation and DNA-damaging agents in preclinical tumour models, offering a clear rationale for clinical evaluation of combination regimens.

DNA Repair Mechanisms in Cancer Therapeutics publication trend

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

Technical terms

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, triggering specialised repair pathways.

Non-homologous end joining (NHEJ): A rapid DSB repair mechanism that ligates broken DNA ends with minimal processing, often active throughout the cell cycle.

Homologous recombination (HR): A high-fidelity DSB repair process using a homologous DNA template, typically engaged in S and G2 phases.

DNA-PKcs: The catalytic subunit of DNA-dependent protein kinase, central to NHEJ and a target for radiosensitising inhibitors.

Radiosensitizer: An agent that increases tumour cell sensitivity to ionising radiation by disrupting DNA damage responses.

References

1. p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice. Nature Communications (2024).
2. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nature Communications (2019).
3. DNA-PKcs inhibitors sensitize neuroendocrine tumor cells to peptide receptor radionuclide therapy in vitro and in vivo. Theranostics (2023).
4. BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer. Journal of Experimental & Clinical Cancer Research (2024).