Cisplatin-induced apoptotic death of CL-V5B cells hypersensitive to cross-linking agents is due to erroneous checkpoint control rather than impaired DNA damage removal (CROSBI ID 548413)
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Podaci o odgovornosti
Brozović, Anamaria ; Damrot, Julia ; Tsaryk, Roman ; Nikolova, Theodora ; Hartig, Cornelia ; Zdzienicka, Malgorzata Z ; Osmak, Maja ; Ross, Wynand ; Kaina, Bernd ; Fritz, Gerhard
engleski
Cisplatin-induced apoptotic death of CL-V5B cells hypersensitive to cross-linking agents is due to erroneous checkpoint control rather than impaired DNA damage removal
A pair of isogenic Chinese hamster cell lines differing in their Fanconi anemia status was used to investigate cisplatin (cDDP)-induced cell death. FANCC defective cells (CL-V5B) are hypersensitive to cDDP, compared to wild type (V79) cells, even though they showed a cca. 50% less initial DNA adduct formation than the wild type. Moreover, cDDP-triggered early stress responses, phosphorylation of histone H2AX and c-jun N-terminal kinase (JNK), are attenuated in CL-V5B cells. However, CL-V5B cells display an excessive G2/M arrest, extensive formation of chromosomal aberrations (CA) and increased formation of gamma-H2AX foci 24 h after cDDP treatment. CL-V5B cells are proficient in DNA adducts removal and show functional homologous recombination, since the frequency of sister chromatid exchanges was similar to this of the wild type. Inhibition of ataxia-telangiectasia mutated kinase /ATM)/ATM and Rad3-related kinase (ATR) signalling by caffeine abrogates G2/M arrest in both cell lines, but only wild type cells were sensitised to cDDP. Thus, our data suggest that S phase-dependent processing of cDDP-induced interstrand cross-links is erroneous in FANCC defective CL-V5B cells, resulting in excessive formation of secondary DNA lesions, which in turn give rise to trapping of cells in G2/M, massive formation of CA and apptotic cell death.
cisplatin; cell death; checkpoint control
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Podaci o prilogu
2008.
objavljeno
Podaci o matičnoj publikaciji
Podaci o skupu
Mechanisms & Models of Cancer
poster
13.08.2008-17.08.2008
Cold Spring Harbor (NY), Sjedinjene Američke Države