O6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo.
Document Type
Article
Publication Date
2009
Keywords
Animals, Apoptosis, Base-Pair-Mismatch, Bone-Marrow-Cells, Cell-Proliferation, DNA-Binding-Proteins, Exodeoxyribonucleases, Fibroblasts, Guanine, Mice-Inbred-C57BL, Mice-Knockout, Spleen, Thymus-Gland
First Page
576
Last Page
581
JAX Source
Proc Natl Acad Sci U S A 2009 Jan; 106(2):576-81.
Abstract
Alkylation-induced O(6)-methylguanine (O(6)MeG) DNA lesions can be mutagenic or cytotoxic if unrepaired by the O(6)MeG-DNA methyltransferase (Mgmt) protein. O(6)MeG pairs with T during DNA replication, and if the O(6)MeG:T mismatch persists, a G:C to A:T transition mutation is fixed at the next replication cycle. O(6)MeG:T mismatch detection by MutSalpha and MutLalpha leads to apoptotic cell death, but the mechanism by which this occurs has been elusive. To explore how mismatch repair mediates O(6)MeG-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 O(6)MeG-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 O(6)MeGs.
Recommended Citation
Klapacz J,
Meira LB,
Luchetti DG,
Calvo JA,
Bronson RT,
Edelmann W,
Samson LD.
O6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo. Proc Natl Acad Sci U S A 2009 Jan; 106(2):576-81.