The genotoxicity of reactive oxygen species (ROS) is well established. The underlying mechanism involves oxidation of DNA by ROS. However, we have recently shown that hydrogen peroxide (H₂O₂), the major mediator of oxidative stress, can also cause genomic damage indirectly. Thus, H₂O₂ at pathologically relevant concentrations rapidly induces higher order chromatin degradation (HOCD), i.e. enzymatic excision of chromatin loops and their oligomers at matrix-attachment regions. The activation of endonuclease that catalyzes HOCD is a signalling event triggered specifically by H₂O₂. The activation is not mediated by an influx of calcium ions, but resting concentrations of intracellular calcium ions are required for the maintenance of the endonuclease in an active form. Although H₂O₂-induced HOCD can efficiently dismantle the genome leading to cell death, under sublethal oxidative stress conditions H₂O₂-induced HOCD may be the major source of somatic mutations.