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DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair.

Publication ,  Journal Article
Drummond, JT; Genschel, J; Wolf, E; Modrich, P
Published in: Proc Natl Acad Sci U S A
September 16, 1997

The level and fate of hMSH3 (human MutS homolog 3) were examined in the promyelocytic leukemia cell line HL-60 and its methotrexate-resistant derivative HL-60R, which is drug resistant by virtue of an amplification event that spans the dihydrofolate reductase (DHFR) and MSH3 genes. Nuclear extracts from HL-60 and HL-60R cells were subjected to an identical, rapid purification protocol that efficiently captures heterodimeric hMutSalpha (hMSH2. hMSH6) and hMutSbeta (hMSH2.hMSH3). In HL-60 extracts the hMutSalpha to hMutSbeta ratio is roughly 6:1, whereas in methotrexate-resistant HL-60R cells the ratio is less than 1:100, due to overproduction of hMSH3 and heterodimer formation of this protein with virtually all the nuclear hMSH2. This shift is associated with marked reduction in the efficiency of base-base mismatch and hypermutability at the hypoxanthine phosphoribosyltransferase (HPRT) locus. Purified hMutSalpha and hMutSbeta display partial overlap in mismatch repair specificity: both participate in repair of a dinucleotide insertion-deletion heterology, but only hMutSalpha restores base-base mismatch repair to extracts of HL-60R cells or hMSH2-deficient LoVo colorectal tumor cells.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

September 16, 1997

Volume

94

Issue

19

Start / End Page

10144 / 10149

Location

United States

Related Subject Headings

  • Tetrahydrofolate Dehydrogenase
  • Nucleic Acid Heteroduplexes
  • Mutation
  • Methotrexate
  • Humans
  • HL-60 Cells
  • Gene Amplification
  • Fungal Proteins
  • Drug Resistance, Microbial
  • DNA-Binding Proteins
 

Citation

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Drummond, J. T., Genschel, J., Wolf, E., & Modrich, P. (1997). DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair. Proc Natl Acad Sci U S A, 94(19), 10144–10149. https://doi.org/10.1073/pnas.94.19.10144
Drummond, J. T., J. Genschel, E. Wolf, and P. Modrich. “DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair.Proc Natl Acad Sci U S A 94, no. 19 (September 16, 1997): 10144–49. https://doi.org/10.1073/pnas.94.19.10144.
Drummond JT, Genschel J, Wolf E, Modrich P. DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10144–9.
Drummond, J. T., et al. “DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair.Proc Natl Acad Sci U S A, vol. 94, no. 19, Sept. 1997, pp. 10144–49. Pubmed, doi:10.1073/pnas.94.19.10144.
Drummond JT, Genschel J, Wolf E, Modrich P. DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10144–10149.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

September 16, 1997

Volume

94

Issue

19

Start / End Page

10144 / 10149

Location

United States

Related Subject Headings

  • Tetrahydrofolate Dehydrogenase
  • Nucleic Acid Heteroduplexes
  • Mutation
  • Methotrexate
  • Humans
  • HL-60 Cells
  • Gene Amplification
  • Fungal Proteins
  • Drug Resistance, Microbial
  • DNA-Binding Proteins