DNA Repair Mechanisms and Cancer Prognostics

Cancer arises in part through the accumulation of DNA lesions that evade normal repair pathways. Cells deploy multiple repair systems—such as base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end joining—to correct distinct forms of damage and maintain genomic stability. Deficiencies or dysregulation in these pathways can drive mutagenesis, tumour initiation and progression. Quantifying the capacity and fidelity of DNA repair in tumours has therefore emerged as a powerful prognostic tool. Measurements of repair-gene expression, functional assays of pathway integrity and analyses of synthetic lethal interactions inform predictions of clinical outcome and guide personalised therapy. Biomarkers derived from repair-factor abundance, mutational signatures and replication-stress responses are increasingly incorporated into risk stratification for patient management, offering insights into likely survival, relapse and treatment response across diverse cancer types.

Research from Nature Portfolio

Recent mechanistic studies of the structure-specific nuclease FEN1 have elucidated how precise substrate selection enforces genome integrity. High-resolution structural and biochemical analyses revealed a ‘phosphate-steering’ mechanism, in which electrostatic interactions guide single-stranded 5′ flaps into the active site and position duplex DNA for incision. Mutations that disrupt this steering drastically reduce catalytic rate and provoke repeat expansions in vivo, uncovering a novel lagging-strand template-switch pathway that underlies genome instability when flap specificity is lost. This work has established phosphate steering as a critical function of FEN1, linking molecular recognition of DNA substrates to prevention of mutational burden and tumourigenesis.

DNA Repair Mechanisms and Cancer Prognostics publication trend

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

Technical terms

Base Excision Repair (BER): Pathway that excises and replaces single-base lesions arising from oxidation, alkylation or deamination.

Homologous Recombination (HR): High-fidelity repair of DNA double-strand breaks using a sister chromatid as template.

Non-Homologous End Joining (NHEJ): Repair of DNA double-strand breaks by direct ligation, without need for homology.

Flap Endonuclease 1 (FEN1): Structure-specific nuclease that removes 5′ flaps during lagging-strand synthesis and long-patch BER.

Synthetic Lethality: Cellular vulnerability arising when co-occurrence of two gene defects leads to cell death but each defect alone is tolerated.

Prognostic Biomarker: A measurable molecular or cellular trait that predicts the natural course and clinical outcome of a disease.

References

1. To cleave or not and how? The DNA exonucleases and endonucleases in immunity. Genes & Diseases (2024).
2. Phosphate steering by Flap Endonuclease 1 promotes 5′-flap specificity and incision to prevent genome instability. Nature Communications (2017).
3. Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma. Disease Markers (2020).
4. The Overexpression of FEN1 and RAD54B May Act as Independent Prognostic Factors of Lung Adenocarcinoma. PLOS ONE (2015).