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 HighlightsO_LIArrest-failed cells result from two routes, each leading to a distinct type C_LIO_LIThese types differ in nuclear morphology, size, ploidy and micronuclei composition C_LIO_LIStrengthening one checkpoint reduces one arrest-failure type but increases the other C_LIO_LITotal error is minimized when checkpoint strengths are suboptimal for each type C_LI eTOCSingle-cell quantitative analyses and computational simulations reveal that the DNA damage checkpoint system balances a tradeoff between reducing arrest failure from diploid cells and from damage-induced polyploid cells. The study suggests that to minimize total arrest failure, the checkpoint strengths need to be sub-optimal for each individual arrest-failure type.