N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate-Induced Chromosome Damage

摘要: Genotoxic tolerance to low-level exposure of monofunctional alkylating agents is compound specific, with the mechanism pertaining alkyl-induced genotoxic threshold response as yet unknown. N-methylpurine DNA glycosylase (MPG), an initiator base excision repair (BER) pathway, typically repairs adducts, many which are associated genomic instability and tumorigenic risk. Here we demonstrate involvement MPG in modulating induced by Sn2 agent ethyl methanesulfonate (EMS) not Sn1 N-ethyl-N-nitrosourea (ENU) human lymphoblastoid cells suggest lack N7-ethylguanine adduct a key factor attributable observed increase EMS-induced chromosome damage. Moreover, messenger RNA expression levels EMS ENU doses administered below low-observed effect level substantiates proposed specific relation genotoxicity. We further report unexpected dose-dependent decrease mutation frequency MPG-deficient cell line M09B when challenged ENU, deemed consequential pronounced number apoptotic relative wild type. Collectively, these findings implicate differential MPG-directed BER primary action for damage cytotoxicity alkane sulfonates N-nitrosourea compounds, respectively.