Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):699–704. doi: 10.1038/sj.bjc.6690412

Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid damaged by cisplatin

B Cenni 1,2, H-K Kim 1, G J Bubley 2, S Aebi 1, D Fink 1, B A Teicher 3,1, S B Howell 1, R D Christen 1
PMCID: PMC2362265  PMID: 10360646

Abstract

In addition to recognizing and repairing mismatched bases in DNA, the mismatch repair (MMR) system also detects cisplatin DNA adducts and loss of MMR results in resistance to cisplatin. A comparison was made of the ability of MMR-proficient and -deficient cells to remove cisplatin adducts from their genome and to reactivate a transiently transfected plasmid that had previously been inactivated by cisplatin to express the firefly luciferase enzyme. MMR deficiency due to loss of hMLH1 function did not change the extent of platinum (Pt) accumulation or kinetics of removal from total cellular DNA. However, MMR-deficient cells, lacking either hMLH1 or hMSH2, generated twofold more luciferase activity from a cisplatin-damaged reporter plasmid than their MMR-proficient counterparts. Thus, detection of the cisplatin adducts by the MMR system reduced the efficiency of reactivation of the damaged luciferase gene compared to cells lacking this detector. The twofold reduction in reactivation efficiency was of the same order of magnitude as the difference in cisplatin sensitivity between the MMR-proficient and -deficient cells. We conclude that although MMR-proficient and -deficient cells remove Pt from their genome at equal rates, the loss of a functional MMR system facilitates the reactivation of a cisplatin-damaged reporter gene. © 1999 Cancer Research Campaign

Keywords: cisplatin, DNA mismatch repair, hMLH1, hMSH2, colon cancer, endometrial cancer

Full Text

The Full Text of this article is available as a PDF (141.9 KB).

Footnotes

Bruno Cenni and Heung-Ki Kim contributed equally to this work.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aebi S., Fink D., Gordon R., Kim H. K., Zheng H., Fink J. L., Howell S. B. Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res. 1997 Oct;3(10):1763–1767. [PubMed] [Google Scholar]
  2. Aebi S., Kurdi-Haidar B., Gordon R., Cenni B., Zheng H., Fink D., Christen R. D., Boland C. R., Koi M., Fishel R. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. 1996 Jul 1;56(13):3087–3090. [PubMed] [Google Scholar]
  3. Ali-Osman F., Berger M. S., Rairkar A., Stein D. E. Enhanced repair of a cisplatin-damaged reporter chloramphenicol-O-acetyltransferase gene and altered activities of DNA polymerases alpha and beta, and DNA ligase in cells of a human malignant glioma following in vivo cisplatin therapy. J Cell Biochem. 1994 Jan;54(1):11–19. doi: 10.1002/jcb.240540103. [DOI] [PubMed] [Google Scholar]
  4. Andrews P. A., Jones J. A., Varki N. M., Howell S. B. Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of human ovarian carcinoma. Cancer Commun. 1990;2(2):93–100. doi: 10.3727/095535490820874641. [DOI] [PubMed] [Google Scholar]
  5. Boyer J. C., Umar A., Risinger J. I., Lipford J. R., Kane M., Yin S., Barrett J. C., Kolodner R. D., Kunkel T. A. Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res. 1995 Dec 15;55(24):6063–6070. [PubMed] [Google Scholar]
  6. Branch P., Aquilina G., Bignami M., Karran P. Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage. Nature. 1993 Apr 15;362(6421):652–654. doi: 10.1038/362652a0. [DOI] [PubMed] [Google Scholar]
  7. Brasier A. R., Tate J. E., Habener J. F. Optimized use of the firefly luciferase assay as a reporter gene in mammalian cell lines. Biotechniques. 1989 Nov-Dec;7(10):1116–1122. [PubMed] [Google Scholar]
  8. Carethers J. M., Hawn M. T., Chauhan D. P., Luce M. C., Marra G., Koi M., Boland C. R. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. J Clin Invest. 1996 Jul 1;98(1):199–206. doi: 10.1172/JCI118767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dijt F. J., Fichtinger-Schepman A. M., Berends F., Reedijk J. Formation and repair of cisplatin-induced adducts to DNA in cultured normal and repair-deficient human fibroblasts. Cancer Res. 1988 Nov 1;48(21):6058–6062. [PubMed] [Google Scholar]
  10. Drummond J. T., Anthoney A., Brown R., Modrich P. Cisplatin and adriamycin resistance are associated with MutLalpha and mismatch repair deficiency in an ovarian tumor cell line. J Biol Chem. 1996 Aug 16;271(33):19645–19648. doi: 10.1074/jbc.271.33.19645. [DOI] [PubMed] [Google Scholar]
  11. Duckett D. R., Drummond J. T., Murchie A. I., Reardon J. T., Sancar A., Lilley D. M., Modrich P. Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6443–6447. doi: 10.1073/pnas.93.13.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eastman A., Schulte N. Enhanced DNA repair as a mechanism of resistance to cis-diamminedichloroplatinum(II). Biochemistry. 1988 Jun 28;27(13):4730–4734. doi: 10.1021/bi00413a022. [DOI] [PubMed] [Google Scholar]
  13. Fink D., Nebel S., Aebi S., Zheng H., Cenni B., Nehmé A., Christen R. D., Howell S. B. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996 Nov 1;56(21):4881–4886. [PubMed] [Google Scholar]
  14. Fink D., Zheng H., Nebel S., Norris P. S., Aebi S., Lin T. P., Nehmé A., Christen R. D., Haas M., MacLeod C. L. In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res. 1997 May 15;57(10):1841–1845. [PubMed] [Google Scholar]
  15. Gately D. P., Howell S. B. Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer. 1993 Jun;67(6):1171–1176. doi: 10.1038/bjc.1993.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hawn M. T., Umar A., Carethers J. M., Marra G., Kunkel T. A., Boland C. R., Koi M. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 1995 Sep 1;55(17):3721–3725. [PubMed] [Google Scholar]
  17. Huang J. C., Zamble D. B., Reardon J. T., Lippard S. J., Sancar A. HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10394–10398. doi: 10.1073/pnas.91.22.10394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jennerwein M. M., Eastman A., Khokhar A. R. The role of DNA repair in resistance of L1210 cells to isomeric 1,2-diaminocyclohexaneplatinum complexes and ultraviolet irradiation. Mutat Res. 1991 Jan;254(1):89–96. doi: 10.1016/0921-8777(91)90044-p. [DOI] [PubMed] [Google Scholar]
  19. Jones J. C., Zhen W. P., Reed E., Parker R. J., Sancar A., Bohr V. A. Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster ovary cells. J Biol Chem. 1991 Apr 15;266(11):7101–7107. [PubMed] [Google Scholar]
  20. Karran P., Bignami M. DNA damage tolerance, mismatch repair and genome instability. Bioessays. 1994 Nov;16(11):833–839. doi: 10.1002/bies.950161110. [DOI] [PubMed] [Google Scholar]
  21. Kat A., Thilly W. G., Fang W. H., Longley M. J., Li G. M., 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. doi: 10.1073/pnas.90.14.6424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koi M., Umar A., Chauhan D. P., Cherian S. P., Carethers J. M., Kunkel T. A., Boland C. R. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 1994 Aug 15;54(16):4308–4312. [PubMed] [Google Scholar]
  23. Kolodner R. D. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397–401. doi: 10.1016/s0968-0004(00)89087-8. [DOI] [PubMed] [Google Scholar]
  24. May A., Nairn R. S., Okumoto D. S., Wassermann K., Stevnsner T., Jones J. C., Bohr V. A. Repair of individual DNA strands in the hamster dihydrofolate reductase gene after treatment with ultraviolet light, alkylating agents, and cisplatin. J Biol Chem. 1993 Jan 25;268(3):1650–1657. [PubMed] [Google Scholar]
  25. Mello J. A., Acharya S., Fishel R., Essigmann J. M. The mismatch-repair protein hMSH2 binds selectively to DNA adducts of the anticancer drug cisplatin. Chem Biol. 1996 Jul;3(7):579–589. doi: 10.1016/s1074-5521(96)90149-0. [DOI] [PubMed] [Google Scholar]
  26. Mello J. A., Lippard S. J., Essigmann J. M. DNA adducts of cis-diamminedichloroplatinum(II) and its trans isomer inhibit RNA polymerase II differentially in vivo. Biochemistry. 1995 Nov 14;34(45):14783–14791. doi: 10.1021/bi00045a020. [DOI] [PubMed] [Google Scholar]
  27. Mu D., Tursun M., Duckett D. R., Drummond J. T., Modrich P., Sancar A. Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems. Mol Cell Biol. 1997 Feb;17(2):760–769. doi: 10.1128/mcb.17.2.760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Parker R. J., Eastman A., Bostick-Bruton F., Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991 Mar;87(3):772–777. doi: 10.1172/JCI115080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sheibani N., Jennerwein M. M., Eastman A. DNA repair in cells sensitive and resistant to cis-diamminedichloroplatinum(II): host cell reactivation of damaged plasmid DNA. Biochemistry. 1989 Apr 4;28(7):3120–3124. doi: 10.1021/bi00433a055. [DOI] [PubMed] [Google Scholar]
  30. Umar A., Koi M., Risinger J. I., Glaab W. E., Tindall K. R., Kolodner R. D., Boland C. R., Barrett J. C., Kunkel T. A. Correction of hypermutability, N-methyl-N'-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res. 1997 Sep 15;57(18):3949–3955. [PubMed] [Google Scholar]
  31. Zamble D. B., Lippard S. J. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem Sci. 1995 Oct;20(10):435–439. doi: 10.1016/s0968-0004(00)89095-7. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES