DNA damage checkpoints balance a tradeoff between diploid- and polyploid-derived arrest failures.

The DNA damage checkpoint system ensures genomic integrity by preventing the division of damaged cells. This system operates primarily through the G1 ∕ S and G2 ∕ M checkpoints, which are susceptible to failure; how these checkpoints coordinate quantitatively to ensure optimal cellular outcomes remains unclear. In this study, we exposed non-cancerous human cells to exogenous DNA damage and used single-cell imaging to monitor spontaneous arrest failure. We discovered that cells fail to arrest in two major paths, resulting in two types with distinct characteristics, including ploidy, nuclear morphology, and micronuclei composition. Computational simulations and experiments revealed strengthening one checkpoint reduced one mode of arrest failure but increased the other, leading to a critical tradeoff for optimizing total arrest failure rates. Our findings suggest optimal checkpoint strengths for minimizing total error are inherently suboptimal for any single failure type, elucidating the systemic cause of genomic instability and tetraploid-like cells in response to DNA damage.