Carcinogenesis, Vol 18, 663-668, Copyright © 1997 by Oxford University Press
F Bernges, A Burkle, JH Kupper and WJ Zeller
Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is a nuclear enzyme
possibly involved in DNA base excision repair. The presence of single- or
double-strand breaks in DNA stimulates this enzyme to covalently modify
acceptor proteins with poly(ADP-ribose) in a reaction that uses NAD+ as
substrate. To test the hypothesis that increased PARP activity could
promote resistance towards DNA-damaging agents and gamma- radiation, we
established stable rat cell transfectants that constitutively express human
PARP. A number of subclones that showed different levels of PARP activity
were isolated from two primary transfectants of different clonal origin.
PARP activity was determined in permeabilized cells after maximal
stimulation with a short, double- stranded oligonucleotide. Activity in
different human PARP-expressing subclones was increased 1.6- to 3.1-fold
compared with non-expressing subclones. In vivo labeling of
poly(ADP-ribose) was performed in one of these subclones, revealing that
the level of poly(ADP-ribose) accumulation after the same treatment with
N-methyl-N'-nitro-N- nitrosoguanidine (MNNG) was four times higher in the
human PARP- expressing subclone compared with both non-expressing
transfected control cells and parental cells. Clonal survival assays
revealed a sensitization upon treatment with gamma-radiation (up to
1.4-fold) or MNNG (up to 2.7-fold) of several subclones expressing human
PARP; in some others survival was not changed. Survival after cisplatin
(DDP) treatment remained essentially unchanged. A protective effect against
DNA-damage was never observed. We conclude that human PARP overexpression
in rodent cells leads to increased poly(ADP- ribosyl)ation capacity and
does not promote survival after gamma- radiation or treatment with the
DNA-damaging agents MNNG or DDP.
ARTICLES
Functional overexpression of human poly(ADP-ribose) polymerase in transfected rat tumor cells
Division 0420, German Cancer Research Center, Heidelberg, Germany.
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