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Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage

Nature volume 362, pages 652654 (15 April 1993) | Download Citation

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Abstract

ACQUIRED resistance to alkylating agents such as N-methyl-N-nitrosourea or N-methyl-N′ -nitro-N-nitrosoguanidine results from the ability to tolerate the potentially cytotoxic methylated base O6-methylguanine (m6-G) in DNA. In the absence of repair by demethylation in situ, m6-G is probably lethal through its inappropriate processing by the cell1. DNA mismatch correction is an attractive candidate for the processing function because although it is replicated, m6-G has no perfect complementary base. Thus, m6-G in DNA might provoke abortive mismatch repair and tolerance could subsequently arise through loss of a mismatch repair pathway2,3. Mismatch correction helps maintain genomic fidelity by removing misincorporated bases and deaminated 5-methylcytosine from DNA, and its loss by mutation confers a mutator phenotype on Escherichia coli4,5. Here we describe human and hamster cell lines that are tolerant to N-methyl-N-nitrosourea and are defective in a DNA mismatch binding activity. The loss of this activity, which acts on G-T mispairs, confers a mutator phenotype.

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Author information

Author notes

    • G. Aquilina
    •  & M. Bignami

    Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

    • P. Karran

    To whom correspondence should be addressed.

Affiliations

  1. Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK

    • P. Branch
    • , G. Aquilina
    • , M. Bignami
    •  & P. Karran

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https://doi.org/10.1038/362652a0

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