Figure 5.

Genotoxin-induced DSBs induce the DNA damage response. Genotoxin-induced DNA double-strand breaks activate ATM/ATR, resulting in phosphorylation of H2AX (γH2AX in magenta), checkpoint protein kinase (CHK) recruitment, activation of DNA repair machineries, and ultimately apoptosis and senescence. Cell cycle arrest results from nuclear exclusion of the phosphatase CDC25 and accumulation of CDK inhibitor p21. Cytoplasmic CDC25 cannot relieve the cyclin-dependent kinase (CDK) from its inhibitory phosphorylation, and CDK-cyclin complexes are further inhibited by p21. Since activation of CDK-cyclin is required for cell cycle progression, activation of the DDR results in cell cycle arrest. In the case of incomplete DNA repair following a chronic or low level of genotoxin exposure, cells accumulate mutations and develop genomic instability.