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

Publication ,  Journal Article
Kat, A; Thilly, WG; Fang, WH; Longley, MJ; Li, GM; Modrich, P
Published in: Proc Natl Acad Sci U S A
July 15, 1993

The human lymphoblastoid MT1 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.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

July 15, 1993

Volume

90

Issue

14

Start / End Page

6424 / 6428

Location

United States

Related Subject Headings

  • Mutation
  • Mutagenesis
  • Hypoxanthine Phosphoribosyltransferase
  • Humans
  • Hela Cells
  • HeLa Cells
  • DNA Repair
  • Cell Nucleus
  • Cell Line
  • B-Lymphocytes
 

Citation

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Kat, A., Thilly, W. G., Fang, W. H., Longley, M. J., Li, G. M., & Modrich, P. (1993). An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci U S A, 90(14), 6424–6428. https://doi.org/10.1073/pnas.90.14.6424
Kat, A., W. G. Thilly, W. H. Fang, M. J. Longley, G. M. Li, and P. Modrich. “An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair.Proc Natl Acad Sci U S A 90, no. 14 (July 15, 1993): 6424–28. https://doi.org/10.1073/pnas.90.14.6424.
Kat A, Thilly WG, Fang WH, Longley MJ, Li GM, Modrich P. An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6424–8.
Kat, A., et al. “An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair.Proc Natl Acad Sci U S A, vol. 90, no. 14, July 1993, pp. 6424–28. Pubmed, doi:10.1073/pnas.90.14.6424.
Kat A, Thilly WG, Fang WH, Longley MJ, Li GM, Modrich P. An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6424–6428.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

July 15, 1993

Volume

90

Issue

14

Start / End Page

6424 / 6428

Location

United States

Related Subject Headings

  • Mutation
  • Mutagenesis
  • Hypoxanthine Phosphoribosyltransferase
  • Humans
  • Hela Cells
  • HeLa Cells
  • DNA Repair
  • Cell Nucleus
  • Cell Line
  • B-Lymphocytes