What ensures that DNA damage is repaired before mitosis?
Faithful genome transmission requires that DNA lesions incurred during replication or from external mutagens be repaired before chromosomes condense and segregate to avoid transmitting broken chromosomes and rearrangements. G2/M checkpoint serves this function by integrating damage sensing with CDK1 control. Lesions such as double-strand breaks recruit MRN complex MRE11-RAD50-NBS1 that activates ATM kinase, while RPA-coated single-stranded DNA from resection or stalled forks recruits ATRIP-ATR and TopBP1 activator. Effector kinases Chk2 and Chk1 phosphorylate dual-specificity phosphatases Cdc25B and Cdc25C at serine 216 generating 14-3-3 binding site sequestering them in cytoplasm away from nuclear cyclin B-CDK1, preserving inhibitory Tyr15 phosphorylation added by Wee1. p53 pathway parallel reinforces arrest via p21, Gadd45, 14-3-3 sigma transcriptional induction. When repair completed through homologous recombination or non-homologous end joining restores duplex, checkpoint kinases inactivated, PP2A dephosphorylates Cdc25, allowing nuclear entry and dephosphorylation of CDK1 driving mitotic entry after genome integrity restored. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.
Ref: Sancar et al., Annu Rev Biochem 2004, DNA Repair Checkpoints. Alberts 7th ed., Chapter 17, G2/M Damage Control.