A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA
Abstract
O(6)-Methylguanine produced in DNA induces mutation due to its ambiguous base-pairing properties during DNA replication. To suppress such an outcome, organisms possess a mechanism to eliminate cells carrying O(6)-methylguanine by inducing apoptosis that requires the function of mismatch repair proteins. To identify other factors involved in this apoptotic process, we performed retrovirus-mediated gene-trap mutagenesis and isolated a mutant that acquired resistance to a simple alkylating agent, N-methyl-N-nitrosourea (MNU). However, it was still sensitive to methyl methanesulfonate, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, etoposide and ultraviolet irradiation. Moreover, the mutant exhibited an increased mutant frequency after exposure to MNU. The gene responsible was identified and designated Mapo1 (O(6)-methylguanine-induced apoptosis 1). When the expression of the gene was inhibited by small interfering RNA, MNU-induced apoptosis was significantly suppressed. In the Mapo1-defective mutant cells treated with MNU, the mitochondrial membrane depolarization and caspase-3 activation were severely suppressed, although phosphorylation of p53, CHK1 and histone H2AX was observed. The orthologs of the M...Continue Reading
References
Genetic studies of the lac repressor. IV. Mutagenic specificity in the lacI gene of Escherichia coli
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Apoptosis
Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis