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Involvement
of the mismatch repair system in temozolomide-induced apoptosis
D'Atri S, Tentori L, Lacal PM, Graziani G, Pagani E,
Benincasa E, Zambruno G, Bonmassar E, Jiricny J
Istituto
Dermopatico Dell'Immacolata, Rome, Italy.
s.datri@idi.it
Postreplicative
mismatch repair plays a major role in mediating the cytotoxicity of agents
generating O6-methylguanine in DNA.
We previously showed that a methylating antitumor triazene compound,
temozolomide, induces apoptosis and that the persistence of O6-methylguanine in
DNA is required to trigger the process.
We wanted to test whether the latter apoptotic signal is dependent on a
functional mismatch repair system.
To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch
repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that
are both deficient in O6-methylguanine repair.
Temozolomide treatment of TK6 cells brought about efficient cell growth
inhibition, G2/M arrest, and apoptosis, as indicated by the results of
cytofluorimetric analysis of 5-bromo-2'-deoxyuridine incorporation and DNA
content and evaluation of DNA fragmentation.
The drug treatment resulted also in the induction of p53 and p21/waf-1 protein
expression.
In contrast, MT1 cells were highly resistant to the drug and no p53 and
p21/waf-1 induction was observed.
Importantly, we could show that MT1 cells are not deficient in the p53-dependent
apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor,
resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell
lines.
In conclusion, we demonstrate the existence of a link between a functional
mismatch repair system and the trigger of apoptosis in cells exposed to
clinically relevant concentrations of temozolomide.
The results also suggest that p53 induction in response to O6-guanine
methylation involves the mismatch repair system.
PMID:
9687575 [PubMed - indexed for MEDLINE]
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