DNA Damage Response and Repair Mechanisms in Cellular Systems

Cells are continually challenged by endogenous processes and environmental agents that inflict lesions on DNA. To preserve genomic integrity, a coordinated DNA damage response (DDR) detects damage, arrests the cell cycle and orchestrates repair. Key sensor kinases such as ATM and ATR phosphorylate histone H2AX around sites of double-strand breaks (DSBs), recruiting mediator proteins and repair complexes. Two principal DSB repair pathways operate: homologous recombination, which uses a sister chromatid as an accurate template, and non-homologous end joining, which ligates broken ends with minimal homology. Additional pathways, including base excision repair, nucleotide excision repair and mismatch repair, correct specific lesion classes. Coupled to these machineries are transcriptional and epigenetic regulators that modulate chromatin accessibility. Together, these processes underpin cellular resilience, influence responses to chemotherapy and radiotherapy, and play central roles in ageing and disease.

Research from Nature Portfolio

Recent studies have elucidated how transcription-associated R-loops contribute to genome instability and how dedicated complexes resolve them. A multicomponent sensor complex recognises single-stranded DNA within R-loops at promoters, stimulating early transcription termination and preventing pathological accumulation of RNA–DNA hybrids. This mechanism acts as a genome surveillance system, attenuating R-loop-induced breaks. In parallel, consensus guidelines for the comet assay have been established, defining essential parameters for sample preparation, electrophoresis and image analysis. These standards enhance reproducibility in quantifying DNA strand breaks and repair kinetics, enabling robust comparisons across laboratories and accelerating the development of DDR inhibitors in preclinical models.

DNA Damage Response and Repair Mechanisms in Cellular Systems publication trend

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

Technical terms

DNA double-strand break: A lesion in which both strands of the DNA helix are severed, activating sensor kinases and repair cascades.

R-loop: A three-stranded structure comprising an RNA–DNA hybrid and displaced single-stranded DNA that can impede replication and transcription.

Homologous recombination: An error-free repair pathway that uses a homologous DNA sequence as a template to restore integrity at breaks.

Non-homologous end joining: A ligation-based repair pathway that rejoins broken DNA ends with minimal or no homology, often introducing mutations.

Comet assay: A single-cell gel electrophoresis technique for visualising and quantifying DNA strand breaks and repair kinetics.

References

1. DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139*. Journal of Biological Chemistry (1998).
2. ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks*. Journal of Biological Chemistry (2001).
3. R-loop-dependent promoter-proximal termination ensures genome stability. Nature (2023).
4. Minimum Information for Reporting on the Comet Assay (MIRCA): recommendations for describing comet assay procedures and results. Nature Protocols (2020).
5. Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling. Signal Transduction and Targeted Therapy (2023).
6. Molecular mechanisms of tumor resistance to radiotherapy. Molecular Cancer (2023).