Does γH2AX foci formation depend on the presence of DNA double strand breaks?

H2AX is a histone variant that is systematically found and ubiquitously distributed throughout the genome. Since it has been reported that DNA double-strand breaks (DSBs) induce phosphorylation of H2AX at serine 139 (γH2AX), an immunocytochemical assay with antibodies recognizing γH2AX has become the gold standard for the detection of DSBs. This assay is quite sensitive and is a specific indicator for the existence of a DSB. Until now, it has been reported that various kinds of physical, chemical, and biological factors induce the formation of the γH2AX foci detected using this assay. Even when γH2AX foci were detected, it was not always possible to conclude that the detected DSBs were produced by environmental stresses in the absence of any known radiation. In this review, emphasis is on discussing whether γH2AX foci formation depends on the formation of DSBs.