An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair

Alexandra Kat, William G. Thilly, Woei Horng Fang, Matthew J. Longley, Guo Min Li, Paul Modrich

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427 Scopus citations


The human lymphoblastoid MTl B-cell line was previously isolated as one of a series of mutant cells able to survive the cytotoxic effects of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). MT1 cells nevertheless remain sensitive to mutagenesis by MNNG and display a mutator phenotype. These phenotypes have been attributed to a single genetic alteration postulated to confer a defect in strand-specific mismatch repair, a proposal that attributes the cytotoxic effect of DNA alkylation in wild-type cells to futile attempts to correct mispairs that arise during replication of alkylated template strands. Our results support this view. MNNG-induced mutations in the HPRT gene of MT1 cells are almost exclusively G·C → A·T transitions, while spontaneous mutations observed in this mutator cell line are single-nucleotide insertions, transversions, and A·T → G·C transitions. In vitro assay has demonstrated that the MT1 line is in fact deficient in strand-specific correction of all eight base-base mispairs. This defect, which is manifest at or prior to the excision stage of the reaction, is due to simple deficiency of a required activity because MT1 nuclear extracts can be complemented by a partially purified HeLa fraction to restore in vitro repair. These findings substantiate the idea that strand-specific mismatch repair contributes to alkylation-induced cytotoxicity and imply that this process serves as a barrier to spontaneous transition, transversion, and insertion/deletion mutations in mammalian cells.

Original languageEnglish (US)
Pages (from-to)6424-6428
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Jul 15 1993


  • Cell death
  • DNA damage
  • DNA repair
  • Mutagenesis

ASJC Scopus subject areas

  • General


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