Does gammaH2AX 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 (gammaH2AX), an immunocytochemical assay with antibodies recognizing gammaH2AX 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 gammaH2AX foci detected using this assay. Even when gammaH2AX 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 gammaH2AX foci formation depends on the formation of DSBs.