In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 2 ( 2009-01-13), p. 576-581
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 MutSα and MutLα 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0811991106
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2009
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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