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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
Open accessAbstract
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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Cites
Frameshift Mutations and the Genetic Code
Streisinger, G., Okada, Y., Emrich, J., Newton, J., Tsugita, A., Terzaghi, E., & Inouye, M. (1966) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1966.031.01.014 · Cited by 1,400
Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair
Marsischky, G. T., Filosi, N., Kane, M. F., & Kolodner, R. (1996) · Genes & Development · doi:10.1101/gad.10.4.407 · Cited by 581
Cited by
DNA Mismatch Repair: Functions and Mechanisms
Iyer, R. R., Pluciennik, A., Burdett, V., & Modrich, P. L. (2006) · Chemical Reviews · doi:10.1021/cr0404794 · Cited by 905
Self-citationDNA MISMATCH REPAIR AND GENETIC INSTABILITY
Harfe, B. D., & Jinks-Robertson, S. (2000) · Annual Review of Genetics · doi:10.1146/annurev.genet.34.1.359 · Cited by 608
The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through Its Interaction with MutSα
Li, F., Mao, G., Tong, D., Huang, J., Gu, L., Yang, W., & Li, G.-M. (2013) · Cell · doi:10.1016/j.cell.2013.03.025 · Cited by 592
Buermeyer, A. B., Deschênes, S. M., Baker, S. M., & Liskay, R. M. (1999) · Annual Review of Genetics · doi:10.1146/annurev.genet.33.1.533 · Cited by 451
Genschel, J., Littman, S. J., Drummond, J. T., & Modrich, P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.31.19895 · Cited by 422
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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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- 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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