DNA MISMATCH REPAIR MUTANTS DO NOT INCREASE N-METHYL-N'-NITRO-N-NITROSOGUANIDINE TOLERANCE IN O-6 METHYLGUANINE DNA METHYLTRANSFERASE-DEFICIENT YEAST-CELLS
W. Xiao et al., DNA MISMATCH REPAIR MUTANTS DO NOT INCREASE N-METHYL-N'-NITRO-N-NITROSOGUANIDINE TOLERANCE IN O-6 METHYLGUANINE DNA METHYLTRANSFERASE-DEFICIENT YEAST-CELLS, Carcinogenesis, 16(8), 1995, pp. 1933-1939
Treatment of cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pr
oduces, among other lesions, mutagenic and carcinogenic lesions such a
s O-6-methylguanine (O(6)MeG) and O-4-methylthymine in DNA, An O(6)MeG
DNA methyl-transferase (MTase) specifically and efficiently repairs s
uch lesions, MTase-deficient bacterial, yeast and mammalian cells exhi
bit increased sensitivity not only to MNNG-induced mutagenesis, but al
so to MNNG-induced kilting, suggesting that O(6)MeG-type lesions are a
lso lethal to the cells, The lethal effect caused by O(6)MeG is not cl
ear, Results from several recent experiments indicate that some MNNG-t
olerant cell lines exhibit a loss of DNA mismatch binding/repair activ
ity, suggesting that functional mismatch repair is probably responsibl
e for the cellular sensitivity to DNA methylating agents, We tested th
is abortive O(6)MeG-T mismatch repair hypothesis in a well-defined low
er eukaryote, Saccharomyces cerevisiae, We found that while mgt1-delet
ed MTase-deficient yeast strains are hypersensitive to MNNG-induced ki
lling, combination of this mutation with any of the mlh1, msh2 or pms1
mutations did not render cells more tolerant to killing, msh3 mutatio
n also did not rescue MNNG-induced genotoxicity. Furthermore, through
the isolation and characterization of MNNG-tolerant cell lines from th
e MTase-deficient mutants we demonstrated that a DNA mismatch repair d
efect is neither sufficient nor required for this process, Since both
DNA repair MTases and mismatch repair proteins are highly conserved be
tween yeast and mammalian cells, our results could suggest alternative
mechanisms in the cellular tolerance to O(6)MeG-induced killing.