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

K Komori1, Y Takagi, M Sanada

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

Oncogene
|January 13, 2009
PubMed

Insights

DNA damage from O(6)-methylguanine can cause mutations. A new gene, Mapo1, is crucial for triggering apoptosis to eliminate these damaged cells, preventing mutations.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • O(6)-methylguanine in DNA causes mutations due to mispairing during replication.
  • Cells eliminate O(6)-methylguanine-containing DNA via apoptosis, requiring mismatch repair proteins.

Purpose of the Study:

  • To identify novel factors involved in the O(6)-methylguanine-induced apoptosis pathway.
  • To characterize a mutant resistant to N-methyl-N-nitrosourea (MNU) and identify the responsible gene.

Main Methods:

  • Retrovirus-mediated gene-trap mutagenesis to isolate resistant mutants.
  • Sensitivity assays with various DNA damaging agents.
  • Gene identification and knockdown using small interfering RNA (siRNA).
  • Analysis of apoptosis markers, including mitochondrial membrane potential and caspase-3 activation.
  • Western blot analysis for p53, CHK1, and histone H2AX phosphorylation.

Main Results:

  • A mutant resistant to MNU but sensitive to other agents was isolated.
  • The responsible gene, Mapo1 (O(6)-methylguanine-induced apoptosis 1), was identified.
  • Mapo1 knockdown significantly suppressed MNU-induced apoptosis.
  • In Mapo1-defective cells, MNU treatment suppressed mitochondrial depolarization and caspase-3 activation, despite p53, CHK1, and H2AX phosphorylation.
  • Mapo1 orthologs are conserved across species, and MAPO1 protein localizes to the cytoplasm.

Conclusions:

  • Mapo1 is essential for initiating apoptosis in response to O(6)-methylguanine-induced DNA damage.
  • Mapo1 functions downstream of DNA damage signaling but upstream of mitochondrial dysfunction and caspase activation.
  • MAPO1 may be a key component in the signal transduction pathway for apoptosis triggered by O(6)-methylguanine mispaired lesions.

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