Effects of 5-methylnicotinamide on mouse L1210 cells exposed to N-methyl-N-nitrosourea: mutation induction, formation and removal of methylation products in DNA, and unscheduled DNA synthesis.
The lethality of N-methyl-N-nitrosourea (MNU) to mouse L1210 cells, as determined by colon forming ability, was potentiated 2.8 fold by the addition of 1 mM 5'-methylnicotinamide (5MeN). When 5MeN was present throughout the expression and selection of 6-thioguanine resistant mutants, the MNU-induced mutation frequency was reduced in duplicate experiments from 15.6 and 12.0 to 7.0 mutants per 10(4) survivors per mM MNU. At the same level of survival, cells treated with 5MeN had approximately 12 times fewer mutants than untreated cells. The rate of removal of the promutagenic lesion O6-methylguanine from DNA was enhanced approximately 2-fold, whereas that of 7-methylguanine was unaffected by the incubation of MNU treated cells with 5MeN. Since 5MeN is a potent inhibitor of poly(ADP-ribose) polymerase, this may imply that in normal cells it is specific ADP-ribosylation of the repair enzyme causing the removal of O6-methylguanine, rather than a more general modification of chromatin structure, that limits the rate of repair of the promutagenic lesion. 5MeN also stimulated unscheduled DNA synthesis in MNU treated cells, implying that an earlier observation that 5MeN prevented rejoining of strand breaks induced by repair of alkyl lesions, probably resulted from inhibition of ligation and not the failure of DNA polymerase to replace bases removed by repair nucleases.
D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism*; D007939:Leukemia L1210 / Q000378:metabolism*; D008745:Methylation; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D009153:Mutagens; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009607:Nitrosourea Compounds / Q000633:toxicity*; D011687:Purines / Q000378:metabolism
D004273:DNA, Neoplasm; D009153:Mutagens; D009607:Nitrosourea Compounds; D011687:Purines; D009536:Niacinamide; D008770:Methylnitrosourea; C024785:5-methylnicotinamide