DNA Damage Response and Genomic Stability in Cancer

Cancer arises not only from the accumulation of mutations in oncogenes and tumour suppressors but also from a failure of the cellular DNA damage response (DDR) to safeguard genomic integrity. The DDR comprises a network of sensors, transducers and effectors that detect DNA lesions, activate cell-cycle checkpoints and coordinate repair or, when damage is irreparable, trigger senescence or apoptosis. Central to maintaining genomic stability is the resolution of replication stress—defined by impeded or stalled replication forks—which, if unaddressed, can lead to double-strand breaks, chromosomal rearrangements or whole-genome doubling. Tumour cells frequently exhibit defects in key repair pathways such as homologous recombination and non-homologous end joining, creating vulnerabilities that can be exploited therapeutically. At the same time, oncogene-induced hyperproliferation drives replication stress and forces cancer cells to rely on residual checkpoint kinases and repair factors to survive. Understanding how these pathways are altered in malignancy has provided insight into novel targets for precision therapies, ranging from inhibitors of checkpoint kinases to agents that further exacerbate replication stress beyond the repair capacity of tumour cells.

Research from Nature Portfolio

Recent studies have revealed that loss of specific cell-surface or structural proteins can undermine homologous recombination, exacerbating chromosomal instability in solid tumours. One investigation demonstrated that alterations in a membrane-associated adhesion molecule diminish homologous recombination efficiency, promote replication stress and drive whole-genome doubling via a dysregulated signalling cascade. Restoration of downstream pathway balance partially rescues numerical instability but not repair fidelity. Another key advance uncovered that oncogene-driven upregulation of general transcription factors elevates global RNA synthesis, leading to R-loop accumulation, replication fork slowing and DNA damage. This work established a direct molecular link between hyperactivated transcription, replication stress and genomic instability, highlighting transcriptional control as a critical mediator of oncogene-induced DNA damage.

DNA Damage Response and Genomic Stability in Cancer publication trend

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

Technical terms

DNA damage response (DDR): A coordinated network of sensing, signalling and repair processes that maintain genome integrity after DNA lesions.

Genomic instability: The increased tendency for mutations, chromosomal rearrangements or copy-number alterations in the genome.

Replication stress: A perturbation of DNA synthesis caused by obstacles that slow or stall replication forks.

Homologous recombination (HR): A high-fidelity repair mechanism that uses an homologous DNA sequence, usually a sister chromatid, to accurately repair breaks.

Checkpoint kinase: A protein that halts cell-cycle progression in response to DNA damage, allowing time for repair or activation of cell-death pathways.

References

1. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling. Nature Cell Biology (2024).
2. Increased global transcription activity as a mechanism of replication stress in cancer. Nature Communications (2016).
3. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell (2023).
4. Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway. Cells (2020).
5. p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways. eLife (2018).