Which checkpoint kinase ensures DNA integrity before mitosis?
Genome surveillance employs two parallel transducer kinases converging on cell cycle arrest before mitosis. ATR-Chk1 pathway responds primarily to single-stranded DNA, stalled forks, base adducts and resected double-strand break ends processed by Exo1 and CtIP nucleases. ATM-Chk2 pathway recognizes blunt double-strand breaks via MRN complex Mre11-Rad50-Nbs1 mediated ATM recruitment and activation at break sites. Activated ATR phosphorylates Chk1, while ATM phosphorylates Chk2 at Thr68 promoting dimerization and full activation through autophosphorylation at Thr383 Thr387 in activation loop. Both Chk1 and Chk2 phosphorylate Cdc25A targeting Thr504 for ubiquitination, Cdc25B and C, creating 14-3-3 docking sites that inactivate phosphatases, thus maintaining CDK1 phosphorylated at Thr14-Tyr15 in inactive state. They also phosphorylate p53 at Ser20 disrupting Mdm2 interaction, stabilizing tumor suppressor to induce p21, GADD45 and 14-3-3 sigma for sustained arrest. Additionally, they phosphorylate BRCA1, Rad51 and histone H2AX, coordinating repair pathway choice with cell cycle delay, preventing transmission of damaged chromosomes into mitosis and preserving genome stability across divisions. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.
Ref: Bartek & Lukas, Chk1 and Chk2 checkpoint kinases, Cancer Cell 2003; NCBI Bookshelf, G2/M DNA Damage Checkpoint.