O. Ullrich et al., Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively damaged histones, P NAS US, 96(11), 1999, pp. 6223-6228
Citations number
30
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
The 20S proteasome has been shown to be largely responsible for the degrada
tion of oxidatively modified proteins in the cytoplasm. Nuclear proteins ar
e also subject to oxidation, and the nucleus of mammalian cells contains pr
oteasome. In human beings, tumor cells frequently are subjected to oxidatio
n as a consequence of antitumor chemotherapy, and K562 human myelogenous le
ukemia cells have a higher nuclear proteasome activity than do nonmalignant
cells, Adaptation to oxidative stress appears to be one element in the dev
elopment of long-term resistance to many chemotherapeutic drugs and the mec
hanisms of inducible tumor resistance to oxidation are of obvious importanc
e, After hydrogen peroxide treatment of K562 cells, degradation of the mode
l proteasome peptide substrate suc-LLVY-MCA and degradation of oxidized his
tones in nuclei increases significantly within minutes. Both increased prot
eolytic susceptibility of the histone substrates (caused by modification by
oxidation) and activation of the proteasome enzyme complex occur independe
ntly during oxidative stress. This rapid upregulation of 20S proteasome act
ivity is accompanied by, and depends on, poly-ADP ribosylation of the prote
asome, as shown by inhibitor experiments, C-14-ADP ribose incorporation ass
ays, immunoblotting, in vitro reconstitution experiments, and immunoprecipi
tation of (activated) proteasome with anti-poly-ADP ribose polymerase antib
odies, The poly-ADP ribosylation-mediated activated nuclear 20S proteasome
is able to remove oxidatively damaged histones more efficiently and therefo
re is proposed as an oxidant-stimulatable defense or repair system of the n
ucleus in K562 leukemia cells.