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DNA mismatch repair deficiency stimulates N-ethyl-N-nitrosourea-induced mutagenesis and lymphomagenesis

Nanna Claij1, Anja van der Wal, Marleen Dekker

  • 1Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.

Cancer Research
|May 3, 2003
PubMed

Insights

The mismatch repair (MMR) system, including MSH2 protein, is crucial for preventing mutations. MMR deficiency enhances mutagenesis from ethylating agents like ENU, suggesting a synergistic role in tumorigenesis.

Area of Science:

  • Molecular Biology
  • Genetics
  • DNA Repair Mechanisms

Background:

  • The mismatch repair (MMR) system corrects replication and recombination errors, and processes DNA lesions like O(6)-methylguanine.
  • Loss of MSH2 protein impairs MMR, reducing cell killing by methylating agents and accelerating mutation accumulation.

Purpose of the Study:

  • To investigate the role of MMR in the cellular response to genotoxic insults beyond methylation.
  • To examine the synergistic interaction between MMR deficiency and ethylating agents in tumorigenesis and mutagenesis.

Main Methods:

  • Comparative analysis of lymphomagenesis in Msh2-deficient and wild-type mice exposed to N-ethyl-N-nitrosourea (ENU).
  • Assessment of ENU lethality and mutagenicity in MSH2-proficient and -deficient mouse embryonic stem cells.
  • Mutation analysis of ENU-induced Hprt mutants to identify mutation types and locations.

Main Results:

  • Msh2-deficient mice exhibited accelerated lymphomagenesis upon ENU exposure, even at non-tumorigenic doses for wild-type mice.
  • MSH2-deficiency slightly reduced ENU lethality but significantly enhanced its mutagenicity in mouse embryonic stem cells.
  • ENU-induced mutations in MSH2-deficient cells predominantly occurred as base substitutions at A-T base pairs.

Conclusions:

  • MMR deficiency and ENU-induced mutagenesis synergistically collaborate in tumorigenesis.
  • MMR plays a significant role in modulating the processing of ethylation damage, particularly at A-T base pairs.

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