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A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA

Oncogene volume 28, pages 1142–1150 (2009)Cite this article

Abstract

O6-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 O6-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 (O6-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 Mapo1 gene are present in various organisms from nematode to humans. Both mouse and human MAPO1 proteins expressed in cells localize in the cytoplasm. We therefore propose that MAPO1 may play a role in the signal-transduction pathway of apoptosis induced by O6-methylguanine-mispaired lesions.

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Acknowledgements

We thank the Kazusa DNA Research Institute for providing hKIAA1450 cDNA. This study was supported by grants (including a Frontier Research Grant) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Molecular Biology, Biomolecular Engineering Research Institute, Suita, Japan

    K Komori, M Sekiguchi & M Hidaka

  2. Frontier Research Center, Fukuoka Dental College, Fukuoka, Japan

    Y Takagi & M Sekiguchi

  3. Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan

    M Sanada & M Hidaka

  4. Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    T-H Lim, Y Nakatsu, T Tsuzuki & M Hidaka

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  1. K Komori
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Correspondence to M Hidaka.

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Komori, K., Takagi, Y., Sanada, M. et al. A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA. Oncogene 28, 1142–1150 (2009). https://doi.org/10.1038/onc.2008.462

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