O. Ullrich et T. Grune, Proteasomal degradation of oxidatively damaged endogenous histones in K562human leukemic cells, FREE RAD B, 31(7), 2001, pp. 887-893
A number of antitumor drugs act via the oxidation of nuclear material in th
e tumor cell. It is therefore important to know if tumor cells can effectiv
ely and precisely cope not only with oxidatively induced DNA damage, but al
so with nuclear protein oxidation. In this study, we investigated the endog
enous degradation of oxidatively damaged histones in K562 human leukemic ce
lls after oxidative challenge and demonstrated a link to the overall cellul
ar stress response pathways by poly-ADP-ribose-polymerase (PARP). After an
oxidative challenge, endogenous nuclear protein degradation, as well as his
tone degradation, was enhanced. Among the histone fractions, histone H1 rev
ealed the highest degradation rate, and more than 85% of the total degraded
H1 disappeared in the first 30 min after oxidative challenge. Short-term d
egradation of histones up to 30 min, as well as long-term degradation up to
48 h after oxidative challenge, was significantly reduced in the presence
of the PARP inhibitor 3-aminobenzamide, and nearly completely abrogated by
the selective proteasome inhibitor lactacystin. Immunoprecipitation experim
ents indicated that the proteasome specifically degraded oxidized histones.
Thus, we show that the nuclear proteosome system in tumor cells is capable
of preventing the accumulation of oxidized proteins in this compartment an
d may suggest further treatment strategies to effectively interfere with th
e protein "repair" and replacement strategies of tumor cells. (C) 2001 Else
vier Science Inc.