DNA Damage Checkpoint Signaling in Eukaryotic Cells

The maintenance of genomic integrity in eukaryotic cells relies on the DNA damage checkpoint, a sophisticated signalling pathway that detects DNA lesions, transduces signals via sensor kinases and adaptor proteins, and coordinates downstream effector kinases to modulate cell cycle progression, DNA repair and, in some cases, apoptosis. At its core, the pathway is initiated by the recognition of DNA damage—particularly double-strand breaks—by sensor complexes such as MRN (Mre11–Rad50–Nbs1) or the 9-1-1 clamp, which recruit the phosphatidylinositol 3-kinase-related kinases ATM and ATR (Tel1 and Mec1 in yeast). Activation of these kinases leads to phosphorylation of adaptor proteins including Rad9/Dpb11, facilitating the activation of effector kinases such as CHK1 and CHK2 (Rad53 in yeast). These effectors propagate signals that transiently arrest the cell cycle at specific checkpoints (G1/S, intra-S and G2/M), allowing DNA repair machinery to restore integrity. Upon successful repair, phosphatases and regulatory factors deactivate the checkpoint to resume cell division. Dysregulation of these pathways contributes to genomic instability, driving oncogenesis and disease progression, while also offering targets for therapeutic intervention in cancer through sensitisation to chemoradiation.

Research from Nature Portfolio

Recent studies have revealed that DNA synthesis can extend into mitosis under certain conditions, challenging the traditional view of strict temporal separation between replication and chromosome segregation. In budding yeast, high cyclin-dependent kinase activity suppresses late-replicating region duplication until mitotic exit, when decreased CDK activity permits completion of DNA replication at subtelomeric and difficult-to-replicate loci. This overlap has been linked to elevated local mutation rates and copy number variation, suggesting a balance between replication fidelity and cellular proliferation rate. These findings provide a framework for understanding how cell cycle dynamics influence genome stability at a population level.

DNA Damage Checkpoint Signaling in Eukaryotic Cells publication trend

The graph below shows the total number of articles in dna damage checkpoint signaling in eukaryotic cells across all publications each year (not limited to Nature Index journals).

Technical terms

DNA damage checkpoint: Protein network that detects DNA lesions and halts cell cycle progression to enable repair.

ATM kinase: Sensor kinase activated by DNA double-strand breaks, initiating checkpoint signalling.

ATR kinase: Sensor kinase responsive to single-stranded DNA regions, activating downstream effectors.

9-1-1 complex: A ring-shaped sensor complex that recognises DNA damage and recruits adaptor proteins.

Spindle assembly checkpoint: Surveillance mechanism ensuring correct chromosome-spindle attachment before anaphase.

References

1. A sterol‐PI(4)P exchanger modulates the Tel1/ATM axis of the DNA damage response. The EMBO Journal (2023).
2. The PP2A phosphatase counteracts the function of the 9-1-1 axis in checkpoint activation. Cell Reports (2023).
3. Prolonged cell cycle arrest in response to DNA damage in yeast requires the maintenance of DNA damage signaling and the spindle assembly checkpoint. eLife (2024).
4. The DNA damage checkpoint: A tale from budding yeast. Frontiers in Genetics (2022).
5. DNA damage checkpoint execution and the rules of its disengagement. Frontiers in Cell and Developmental Biology (2022).
6. Budding yeast complete DNA synthesis after chromosome segregation begins. Nature Communications (2020).