L-DNASE-II, A MOLECULE THAT LINKS PROTEASES AND ENDONUCLEASES IN APOPTOSIS, DERIVES FROM THE UBIQUITOUS SERPIN LEUKOCYTE ELASTASE INHIBITOR

The most widely recognized biochemical change associated with the majo rity of apoptotic systems is the degradation of genomic DNA, Among the enzymes that may participate in this cleavage, the acidic cation-inde pendent DNase II is a likely candidate since it is activated in many a poptotic cells, To better understand its role, we purified and sequenc ed a DNase II extracted from porcine spleen, Protein sequencing of ran dom peptides demonstrated that this enzyme is derived from a ubiquitou s serpin, the leukocyte elastase inhibitor (LEI), by an acidic-depende nt posttranslational modification or by digestion with elastase. We ca ll this novel enzyme L-DNase II. In vitro experiments with purified re combinant LEI show that the native form has no effect on purified nucl ei whereas its posttranslationally activated form induces pycnosis and DNA degradation. Antibodies directed against L-DNase II showed, in di fferent cell lines, an increased expression and a nuclear translocatio n of this enzyme during apoptosis. Since the appearance of the endonuc lease activity results in a loss of the anti-protease properties of LE I, the transformation from LEI to L-DNase II may act as a switch of pr otease and nuclease pathways, each of which is activated during apopto sis.