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Cited by 158

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DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSα/hMutSβ ratio and reduces the efficiency of base–base mismatch repair

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Drummond, James T., Genschel, Jochen, Wolf, Elisabeth, Modrich, Paul·1997·Proceedings of the National Academy of Sciences

Abstract

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 hMutSα (hMSH2⋅hMSH6) and hMutSβ (hMSH2⋅hMSH3). In HL-60 extracts the hMutSα to hMutSβ 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 hMutSα and hMutSβ display partial overlap in mismatch repair specificity: both participate in repair of a dinucleotide insertion–deletion heterology, but only hMutSα restores base–base mismatch repair to extracts of HL-60R cells or hMSH2-deficient LoVo colorectal tumor cells.

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Metadata

Authors
Drummond, J. T., Genschel, J., Wolf, E., & Modrich, P.
Venue
Proceedings of the National Academy of Sciences
Published
1997-09-16
Volume
94
Issue
19
Pages
10144-10149
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2137334007
Cited by
158
References
2
FWCI
3.71
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSα/hMutSβ ratio and reduces the efficiency of base–base mismatch repair. https://app.cochat.ai/papers/10.1073/pnas.94.19.10144
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Drummond, J. T., Genschel, J., Wolf, E., & Modrich, P. (1997). DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSα/hMutSβ ratio and reduces the efficiency of base–base mismatch repair. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.94.19.10144

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