DNA Break Repair Mechanisms in Eukaryotic Cells

Genome integrity in eukaryotic cells depends on the timely detection and faithful repair of DNA double-strand breaks (DSBs), which arise from exogenous insults, replication stress and programmed processes. Two principal pathways oversee DSB resolution: non-homologous end joining (NHEJ), which ligates DNA ends with minimal processing and operates throughout the cell cycle, and homologous recombination (HR), which uses a sister chromatid as a template during S and G2 phases to ensure high-fidelity repair. A balance between these pathways is achieved through cell-cycle control, end-resection kinetics and regulatory post-translational modifications. Key sensor proteins, notably the MRN complex (Mre11–Rad50–Nbs1), recruit kinases such as ATM to phosphorylate downstream effectors and initiate end processing. End resection, mediated by CtIP in conjunction with Mre11 and extended by nucleases Exo1 or Dna2–BTR complex, generates 3′ single-stranded DNA that is stabilised by RPA and subsequently handed off to RAD51 for strand invasion and homology search. In contrast, NHEJ relies on the Ku70–Ku80 heterodimer and DNA-PKcs to protect ends, with ligation executed by XRCC4–Ligase IV. Alternative end joining and single-strand annealing serve as backup pathways when canonical routes are compromised, albeit with increased mutagenic potential. Recent work has illuminated layers of regulation, including PARP-mediated signalling, ubiquitin-dependent turnover of repair factors and the interplay between reactive oxygen species and checkpoint responses, underscoring the dynamic crosstalk that maintains genomic stability and influences cancer susceptibility, ageing and therapeutic resistance.

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DNA Break Repair Mechanisms in Eukaryotic Cells publication trend

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Technical terms

Double-strand break (DSB): A DNA lesion in which both strands of the double helix are severed.

Homologous recombination (HR): A high-fidelity repair pathway that uses a homologous DNA sequence as a template.

Non-homologous end joining (NHEJ): A repair pathway that directly ligates DNA ends with little or no homology requirement.

Resection: The nucleolytic processing of DNA ends to generate 3′ single-stranded DNA tails.

Poly(ADP-ribose) polymerase (PARP): An enzyme that adds ADP-ribose polymers to target proteins in response to DNA damage.

CtIP: A critical factor that promotes end resection and directs DSB repair pathway choice.

MRN complex: A trimeric sensor (Mre11–Rad50–Nbs1) that recognises DSBs and activates checkpoint kinases.

References

1. NUDT16 regulates CtIP PARylation to dictate homologous recombination repair. Nucleic Acids Research (2024).
2. A noncanonical response to replication stress protects genome stability through ROS production, in an adaptive manner. Cell Death & Differentiation (2023).
3. The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication. Molecular Cell (2018).
4. How cells ensure correct repair of DNA double-strand breaks. Journal of Biological Chemistry (2018).
5. DNA End Resection: Nucleases Team Up with the Right Partners to Initiate Homologous Recombination*. Journal of Biological Chemistry (2015).