O6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo

Joanna Klapacz, Lisiane B. Meira, David G. Luchetti, Jennifer A. Calvo, Roderick T. Bronson, Winfried Edelmann, Leona D. Samson

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Alkylation-induced O6-methylguanine (O6MeG) DNA lesions can be mutagenic or cytotoxic if unrepaired by the O6MeG-DNA methyltransferase (Mgmt) protein. O6MeG pairs with T during DNA replication, and if the O6MeG:T mismatch persists, a G:C to A:T transition mutation is fixed at the next replication cycle. O6MeG:T mismatch detection by MutSα and MutLα leads to apoptotic cell death, but the mechanism by which this occurs has been elusive. To explore how mismatch repair mediates O6MeG-dependent apoptosis, we used an Mgmt-null mouse model combined with either the Msh6-null mutant (defective in mismatch recognition) or the Exo1-null mutant (impaired in the excision step of mismatch repair). Mouse embryonic fibroblasts and bone marrow cells derived from Mgmt-null mice were much more alkylation-sensitive than wild type, as expected. However, ablation of either Msh6 or Exo1 function rendered these Mgmt-null cells just as resistant to alkylation-induced cytotoxicity as wild-type cells. Rapidly proliferating tissues in Mgmt-null mice (bone marrow, thymus, and spleen) are extremely sensitive to apoptosis induced by O6MeG- producing agents. Here, we show that ablation of either Msh6 or Exo1 function in the Mgmt-null mouse renders these rapidly proliferating tissues alkylation-resistant. However, whereas the Msh6 defect confers total alkylation resistance, the Exo1 defect leads to a variable tissue-specific alkylation resistance phenotype. Our results indicate that Exo1 plays an important role in the induction of apoptosis by unrepaired O6MeGs.

Original languageEnglish (US)
Pages (from-to)576-581
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - Jan 13 2009

Keywords

  • Alkylation resistance
  • Apoptosis
  • DNA alkylation
  • Mgmt
  • N-methyl-N′- nitrosourea (MNU)

ASJC Scopus subject areas

  • General

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