SPECIFIC CLEAVAGE OF THE LARGE SUBUNIT OF REPLICATION FACTOR-C IN APOPTOSIS IS MEDIATED BY CPP32-LIKE PROTEASE

Recent evidence suggests that the growing family of cysteine proteases related to the interleukin-1 beta-converting enzyme (ICE) is of centr al importance in mediating apoptosis, Proteolytic cleavage of a small group of cellular substrates by these enzymes in association with the onset of apoptosis has been reported. In the present study, we searche d a protein data base for potential death substrates possessing the CP P32 cleavage site, DEVD, and identified several candidates including R FC140, the large subunit of replication factor C, which we subsequentl y demonstrated to be specifically cleaved in a variety of cell types u ndergoing apoptosis in response to different cytotoxic agents, whereas no degradation is observed in a cell line resistant to etoposide-indu ced apoptosis, The abrogation of RFC140 cleavage in apoptotic extracts by Ac-DEVD-CHO, a potent inhibitor of CPP32, together with the findin g that a CPP32 consensus cleavage sequence, DEVD, exists in RFC140, su ggests that CPP32 or a close relative is responsible for RFC140 degrad ation in apoptosis, (C) 1997 Academic Press.