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

ABSTRACT: The DNA damage checkpoint system ensures genomic integrity by preventing the division of damaged cells, primarily through the G1/S and G2/M checkpoints. How these checkpoints collectively minimize error remains unclear. Here, we exposed non-cancerous human cells to DNA damage and used single-cell imaging to monitor spontaneous arrest failure. Under intermediate damage, cells divided with error via two major routes: one involving mitotic skipping (extensive engagement of the G2/M checkpoint) followed by endoreplication (escape from G1/S), and the second involving escape from the G2/M checkpoint. These pathways produced distinct ploidy, nuclear morphology, and micronuclei composition. Simulations and experiments showed that strengthening one checkpoint reduced one failure mode but exacerbate

SUBMITTER: Fujimaki K 

PROVIDER: S-EPMC12666768 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature