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- W2076360528 abstract "Monofunctional alkylating agents react with DNA by SN1 or SN2 mechanisms resulting in formation of a wide spectrum of cytotoxic base adducts. DNA polymerase β (β-pol) is required for efficient base excision repair of N-alkyl adducts, and we make use of the hypersensitivity of β-pol null mouse fibroblasts to investigate such alkylating agents with a view towards understanding the DNA lesions responsible for the cellular phenotype. The inability of O6-benzylguanine to sensitize wild-type or β-pol null cells to SN1-type methylating agents indicates that the observed hypersensitivity is not due to differential repair of cytotoxic O-alkyl adducts. Using a 3-methyladenine-specific agent and an inhibitor of such methylation, we find that inefficient repair of 3-methyladenine is not the reason for the hypersensitivity of β-pol null cells to methylating agents, and further that 3-methyladenine is not the adduct primarily responsible for methyl methanesulfonate (MMS)- and methyl nitrosourea-induced cytotoxicity in wild-type cells. Relating the expected spectrum of DNA adducts and the relative sensitivity of cells to monofunctional alkylating agents, we propose that the hypersensitivity of β-pol null cells reflects accumulation of cytotoxic repair intermediates, such as the 5′-deoxyribose phosphate group, following removal of 7-alkylguanine from DNA. In support of this conclusion, β-pol null cells are also hypersensitive to the thymidine analog 5-hydroxymethyl-2′-deoxyuridine (hmdUrd). This agent is incorporated into cellular DNA and elicits cytotoxicity only when removed by glycosylase-initiated base excision repair. Consistent with the hypothesis that there is a common repair intermediate resulting in cytotoxicity following treatment with both types of agents, both MMS and hmdUrd-initiated cell death are preceded by a similar rapid concentration-dependent suppression of DNA synthesis and a later cell cycle arrest in G0/G1 and G2M phases." @default.
- W2076360528 created "2016-06-24" @default.
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- W2076360528 date "2003-01-01" @default.
- W2076360528 modified "2023-10-14" @default.
- W2076360528 title "Hypersensitivity of DNA polymerase β null mouse fibroblasts reflects accumulation of cytotoxic repair intermediates from site-specific alkyl DNA lesions" @default.
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- W2076360528 doi "https://doi.org/10.1016/s1568-7864(02)00184-2" @default.
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