The discovery of the internucleosomal fragmentation of genomic DNA to regular repeating oligonucleosomal fragments generated by Ca/Mg-dependent endonuclease is accepted as one of the best-characterized biochemical markers of apoptosis (programmed cell death).
In 1970,  described that cytoplasmic DNA isolated from mouse liver cells after culture was characterized by DNA fragments with a molecular weight consisting of multiples of 135 kDa. This finding was consistent with the hypothesis that these DNA fragments were a specific degradation product of nuclear DNA. In 1972, , , and  coined the term apoptosis and distinguished this type of cell death from necrosis based on morphological features. In 1973,  and , during the study of subchromatin structure, found that chromatin is accessible to the Ca/Mg endonuclease, resulting in the formation of a digestion product with a regular series of molecular weight similar to the one previously described by Williamson (1970). In 1974, , , and , using cells exposed to widely differing types of trauma, found that during cell death, degraded DNA in "every case had a modal value of between 10(x6) and 10(x7)  Dalton and cellular metabolism is required to produce degradation of DNA". However, this observation was without indication of "whether the incision attack on the DNA molecule was a random or rather at a particular site, that have structural or functional meaning". In 1976, , , and  described internucleosomal fragmentation of irradiated lymphoid chromatin DNA in vivo.
Six years passed from 1972 to 1978/1980 until the discovery and evaluation of internucleosomal fragmentation of DNA during apoptotic cell death as a hallmark of apoptosis. Since 1972 (, , and ), it is accepted that glucocorticoid-induced death of lymphocytes is a form of apoptosis. In 1978,  and  presented a paper revealing that glucocorticoid-induced DNA degradation in rat lymphoid tissue, thymus, and spleen occurred in a specific pattern producing fragments of DNA that were electrophoretically similar to those observed after treatment of chromatin with microccoccal nuclease, which indicated internucleosomal cleavage pattern of DNA degradation occurred during apoptosis. Thus, the first link between programmed cell death/apoptosis and internucleosomal fragmentation of chromatin DNA was discovered and soon became as a specific feature of apoptosis.
In 1980,  reported additional evidence for an internucleosomal DNA cleavage pattern as a specific feature of glucocorticoid-treated thymocytes undergoing apoptosis. The internucleosomal DNA cleavage pattern was observed as a specific feature of apoptosis in 1978/1980 and has become a recognised hallmark of programmed cell death since then. In 1992 Gorczyca et al.  and Gavrieli et al. independently described the DNA fragmentation assay based on the use of the terminal deoxynucleotidyl transferase (TUNEL) which become one of the standard methods to detect and identify apoptotic cells.