DNA Double-Strand Breaks and Genomic Stability

DNA double-strand breaks (DSBs) represent a critical form of damage in which both strands of the DNA helix are severed. If left unrepaired or misrepaired, DSBs can lead to chromosomal translocations, deletions and genomic instability that underlie cancer, ageing and a spectrum of genetic disorders. Cells deploy two principal repair pathways: homologous recombination (HR), which uses a homologous template to restore sequence fidelity, and non-homologous end joining (NHEJ), which ligates broken ends more rapidly but with a higher risk of sequence alterations. A sophisticated network of sensors and transducers—including the histone variant γH2AX and kinases such as ATM and DNA-PK—coordinates cell-cycle checkpoints, chromatin remodelling and repair enzyme recruitment. Recent advances in genome-wide break mapping and quantitative sequencing have transformed our understanding of DSB formation, distribution and repair kinetics. These insights are reshaping therapeutic strategies in oncology, guiding the design of DNA damage response inhibitors and informing risk assessment for environmental genotoxins. By integrating mechanistic detail with technological innovation, current research continues to illuminate how DSB repair pathways preserve genome integrity while balancing the need for physiological DNA transactions such as transcription and replication.

Research from Nature Portfolio

Quantitative DSB sequencing (qDSB-Seq) has provided an absolute measure of break frequency per cell alongside precise genomic coordinates, revealing two- to three-order-of-magnitude differences in DSB induction by radiomimetic drugs and replication stress. This method standardises spike-in breaks to enable accurate comparison of DSB burdens across samples and conditions. A nucleotide-resolution map of Topoisomerase II (Top2)-linked DNA breaks in yeast and human cells has uncovered two distinct classes of Top2 activity in human genomes: tightly localised events near architectural proteins such as CTCF and broadly distributed breaks in transcription-proximal regions, the latter correlating with gene length and expression level. Foundational work on transcriptional elongation has established that DNA damage response signalling is integral to Pol II release from promoter-proximal pausing. This mechanism involves TRIM28 phosphorylation by DNA-PK, ATM-mediated γH2AX deposition and Top2 activity, demonstrating that controlled DSB formation is required for efficient transcription of stimulus-inducible genes.

DNA Double-Strand Breaks and Genomic Stability publication trend

The graph below shows the total number of articles in dna double-strand breaks and genomic stability 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, posing a severe threat to genome integrity.

γH2AX: Phosphorylated histone H2AX that marks chromatin around DSBs and recruits repair factors.

Homologous recombination (HR): A high-fidelity repair pathway using a homologous DNA template to restore sequence accuracy at a break.

Non-homologous end joining (NHEJ): A rapid repair process that ligates DNA ends directly, often with small insertions or deletions.

Topoisomerase II (Top2): An enzyme that relieves DNA supercoiling by transiently breaking and rejoining both strands of the helix.

qDSB-Seq: Quantitative DSB sequencing, a method that uses spike-in breaks to measure absolute DSB frequencies per cell and map their positions.

FaCIN: DNA fragility–associated chromatin interaction network, a three-dimensional motif linking long-range contacts to local break susceptibility.

References

1. A graph neural network-based interpretable framework reveals a novel DNA fragility–associated chromatin structural unit. Genome Biology (2023).
2. To Break or Not to Break: The Role of TOP2B in Transcription. International Journal of Molecular Sciences (2023).
3. Let’s not take DNA breaks for granted. The importance of direct detection of DNA breaks for the successful development of DDR inhibitors. Frontiers in Cell and Developmental Biology (2023).
4. DNA fragility at the KMT2A/MLL locus: insights from old and new technologies. Open Biology (2023).
5. Multiple facets of histone variant H2AX: a DNA double-strand-break marker with several biological functions. Nucleic Acids Research (2015).
6. Transcriptional elongation requires DNA break-induced signalling. Nature Communications (2015).
7. A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome. Nature Communications (2019).
8. qDSB-Seq is a general method for genome-wide quantification of DNA double-strand breaks using sequencing. Nature Communications (2019).