Specific Proteolytic Processing of Poly(ADP-Ribose) Polymerase in Human Lymphocytes

Abstract

Four enzymatic systems have been described that directly and selectively affect cellular metabolism of poly(ADP-ribosyl)ated proteins. (1) The enzyme poly(ADP-ribose) polymerase cleaves nicotinamide from NAD and then forms a covalent linkage between the residual ADP-ribose moiety and specific protein acceptor molecules [1,2]. The same enzyme can add successive ADP-ribose moieties to form homopolymers in excess of 100 residues with alternating phosphodiester and O-glycosidic linkages. (2) Poly(ADP-ribose) glycohydrolase degrades poly(ADP-ribose) at the O-glycosidic linkages in an exoglycosidic fashion [3,4]. This appears to be the major cellular enzyme responsible for polymer degradation. (3) Phosphodiesterases degrade the polymer at the phosphodiester bonds. Some phosphodiesterases function as endonucleases and others as exonucleases [5,6]. However, these enzymes do not appear to play an important role in cellular modulation of poly(ADP-ribose) levels. (4) Poly(ADP-ribose)-protein hydrolase specifically hydrolyzes the covalent linkage between proteins and ADP-ribose [7]. The physiological importance of this enzyme has recently been suggested by the identification of a lysosomal storage disease in which glutamyl ribose 5-phosphate accumulates in tissues, presumably due to a genetic deficiency of this enzyme [8]. Our studies in human lymphocytes reveal that a nucleotide and/or pyrophosphate stimulated proteolytic processing system constitutes a fifth enzymatic pathway for selective modulation of poly(ADP-ribosyl)ated proteins.