PMID: 9434879Jan 22, 1998Paper

Chromosomal instability, reproductive cell death and apoptosis induced by O6-methylguanine in Mex-, Mex+ and methylation-tolerant mismatch repair compromised cells: facts and models

Mutation Research
B KainaT Coquerelle

Abstract

O6-Methylguanine (O6-MeG) is induced in DNA by methylating environmental carcinogens and various cytostatic drugs. It is repaired by O6-methylguanine-DNA methyltransferase (MGMT). If not repaired prior to replication, the lesion generates gene mutations and leads to cell death, sister chromatid exchanges (SCEs), chromosomal aberrations and malignant transformation. To address the question of how O6-MeG is transformed into genotoxic effects, isogenic Chinese hamster cell lines either not expressing MGMT (phenotypically Mex-), expressing MGMT (Mex+) or exhibiting the tolerance phenotype (Mex-, methylation resistant) were compared as to their clastogenic response. Mex- cells were more sensitive than Mex+ cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chromosomal breakage, with marked differences in sensitivity depending on recovery time. At early recovery time, when cells out of the first post-treatment mitosis were scored, aberration frequency was about 40% reduced in Mex+ as compared to Mex- cells. At later stages of recovery when cells out of the second post-treatment mitosis were analyzed, the frequency of aberrations increased strongly in Mex- cells whereas it dropped to nearly control level in Mex+ cells. From ...Continue Reading

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