The human brm (hbrm) protein (homologue of the Drosophila melanogaster brah
ma and Saccharomyces cervisiae SNF-2 proteins) is part of a polypeptide com
plex believed to regulate chromatin conformation. We have shown that the hb
rm protein is cleaved in NB4 leukemic cells after induction of apoptosis by
UV-irradiation, DNA damaging agents, or staurosporine, Because hbrm is fou
nd only in the nucleus, we have investigated the nature of the proteases th
at may regulate the degradation of this protein during apoptosis. In an in
vitro assay, the hbrm protein could not be cleaved by caspase-3, -7, or -6,
the "effector" caspases generally believed to carry out the cleavage of nu
clear protein substrates. In contrast, we find that cathepsin G, a granule
enzyme found in NB4 cells, cleaves hbrm in a pattern similar to that observ
ed in vivo during apoptosis. In addition, a peptide inhibitor of cathepsin
C blocks hbrm cleavage during apoptosis but does not block activation of ca
spases or cleavage of the nuclear protein polyADP ribose polymerase (PARP).
Although localized in granules and in the Golgi complex in untreated cells
, cathepsin G becomes diffusely distributed during apoptosis. Cleavage by c
athepsin C removes a 20-kDa fragment containing a bromodomain from the carb
oxyl terminus of hbrm, This cleavage disrupts the association between hbrm
and the nuclear matrix; the 160-kDa hbrm cleavage fragment is less tightly
associated with the nuclear matrix than full-length hbrm.