New aspects of the mechanism of DNA fragmentation in apoptosis.

In this article we review the current status of research into the mechanism of DNA fragmentation in apoptosis. There is accumulating evidence that there is no single conserved endonuclease that is responsible for DNA fragmentation in all cells. Not only are the two stages of high molecular weight fragment and DNA ladder formation likely to be catalysed by different activities, but multiple activities appear to be involved in internucleosomal DNA fragmentation in various cells. In addition to any one of a number of Ca2+/Mg2+-dependent endonucleases, acidic enzymes (i.e., endonucleases that are active at acid pH) also appear to be involved. Moreover, some enzymes currently being identified are active over a broad range of acidic and neutral pH values and have complex cation requirements that are a function of pH. DNA fragmentation in apoptosis appears to be controlled by either Ca2+ ions or a decrease in pH, depending on the cell type. DNA degradation to oligonucleosomes is not essential for apoptosis, but all cells must undergo DNA degradation to produce the large fragments. This is believed to occur in regions of DNA attached to the nuclear matrix, but the activity responsible has not yet been identified. Changes in both Ca2+ ions and pH have been recorded in a variety of cells, indicating that both mechanisms of regulation of endonuclease activation are involved in apoptosis.