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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 May;87(9):3522–3525. doi: 10.1073/pnas.87.9.3522

Molecular mechanisms of DNA repair inhibition by caffeine.

C P Selby 1, A Sancar 1
PMCID: PMC53933  PMID: 2185474

Abstract

Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

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Selected References

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  1. Bjelland S., Seeberg E. Purification and characterization of 3-methyladenine DNA glycosylase I from Escherichia coli. Nucleic Acids Res. 1987 Apr 10;15(7):2787–2801. doi: 10.1093/nar/15.7.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Day R. S., 3rd Caffeine inhibition of the repair of ultraviolet-irradiated adenovirus in human cells. Mutat Res. 1975 Dec;33(2-3):321–326. doi: 10.1016/0027-5107(75)90207-9. [DOI] [PubMed] [Google Scholar]
  3. Domon M., Barton B., Porte A., Rauth A. M. The interaction of caffeine with ultra-violet-light-irradiated DNA. Int J Radiat Biol Relat Stud Phys Chem Med. 1970;17(4):395–399. doi: 10.1080/09553007014550481. [DOI] [PubMed] [Google Scholar]
  4. Fritzsche H., Petri I., Schütz H., Weller K., Sedmera P., Lang H. On the interaction of caffeine with nucleic acids. III. 1H NMR studies of caffeine--5'-adenosine monophosphate and caffeine-poly(riboadenylate) interactions. Biophys Chem. 1980 Feb;11(1):109–119. doi: 10.1016/0301-4622(80)85013-7. [DOI] [PubMed] [Google Scholar]
  5. Harm W. Analysis of photoenzymatic repair of UV lesions in DNA by single light flashes. 8. Inhibition of photoenzymatic repair of UV lesions in E. coli DNA by caffeine. Mutat Res. 1970 Oct;10(4):319–333. doi: 10.1016/0027-5107(70)90046-1. [DOI] [PubMed] [Google Scholar]
  6. Husain I., Griffith J., Sancar A. Thymine dimers bend DNA. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2558–2562. doi: 10.1073/pnas.85.8.2558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Husain I., Sancar G. B., Holbrook S. R., Sancar A. Mechanism of damage recognition by Escherichia coli DNA photolyase. J Biol Chem. 1987 Sep 25;262(27):13188–13197. [PubMed] [Google Scholar]
  8. Kan L. S., Borer P. N., Cheng D. M., Ts'o P. O. 1H- and 13C-NMR studies on caffeine and its interaction with nucleic acids. Biopolymers. 1980 Sep;19(9):1641–1654. doi: 10.1002/bip.1980.360190908. [DOI] [PubMed] [Google Scholar]
  9. Kane C. M., Linn S. Purification and characterization of an apurinic/apyrimidinic endonuclease from HeLa cells. J Biol Chem. 1981 Apr 10;256(7):3405–3414. [PubMed] [Google Scholar]
  10. Kaplan J. C., Kushner S. R., Grossman L. Enzymatic repair of DNA. 3. Properties of the UV-endonuclease and UV-exonuclease. Biochemistry. 1971 Aug 31;10(18):3315–3324. doi: 10.1021/bi00794a001. [DOI] [PubMed] [Google Scholar]
  11. Lambert B., Jones B. K., Roques B. P., Le Pecq J. B., Yeung A. T. The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6557–6561. doi: 10.1073/pnas.86.17.6557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lane M. J., Dabrowiak J. C., Vournakis J. N. Sequence specificity of actinomycin D and Netropsin binding to pBR322 DNA analyzed by protection from DNase I. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3260–3264. doi: 10.1073/pnas.80.11.3260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Neidle S., Abraham Z. Structural and sequence-dependent aspects of drug intercalation into nucleic acids. CRC Crit Rev Biochem. 1984;17(1):73–121. doi: 10.3109/10409238409110270. [DOI] [PubMed] [Google Scholar]
  14. Nielsen P. E., Zhen W. P., Henriksen U., Buchardt O. Sequence-influenced interactions of oligoacridines with DNA detected by retarded gel electrophoretic migrations. Biochemistry. 1988 Jan 12;27(1):67–73. doi: 10.1021/bi00401a012. [DOI] [PubMed] [Google Scholar]
  15. Orren D. K., Sancar A. The (A)BC excinuclease of Escherichia coli has only the UvrB and UvrC subunits in the incision complex. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5237–5241. doi: 10.1073/pnas.86.14.5237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sancar A., Sancar G. B. DNA repair enzymes. Annu Rev Biochem. 1988;57:29–67. doi: 10.1146/annurev.bi.57.070188.000333. [DOI] [PubMed] [Google Scholar]
  17. Sancar A., Sancar G. B. Escherichia coli DNA photolyase is a flavoprotein. J Mol Biol. 1984 Jan 15;172(2):223–227. doi: 10.1016/s0022-2836(84)80040-6. [DOI] [PubMed] [Google Scholar]
  18. Seeberg E., Strike P. Excision repair of ultraviolet-irradiated deoxyribonucleic acid in plasmolyzed cells of Escherichia coli. J Bacteriol. 1976 Mar;125(3):787–795. doi: 10.1128/jb.125.3.787-795.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Thomas D. C., Levy M., Sancar A. Amplification and purification of UvrA, UvrB, and UvrC proteins of Escherichia coli. J Biol Chem. 1985 Aug 15;260(17):9875–9883. [PubMed] [Google Scholar]
  20. Timson J. Caffeine. Mutat Res. 1977;47(1):1–52. doi: 10.1016/0165-1110(77)90016-1. [DOI] [PubMed] [Google Scholar]
  21. Tornaletti S., Russo P., Parodi S., Pedrini A. M. Studies on DNA binding of caffeine and derivatives: evidence of intercalation by DNA-unwinding experiments. Biochim Biophys Acta. 1989 Jan 23;1007(1):112–115. doi: 10.1016/0167-4781(89)90138-3. [DOI] [PubMed] [Google Scholar]
  22. Van Houten B., Gamper H., Hearst J. E., Sancar A. Analysis of sequential steps of nucleotide excision repair in Escherichia coli using synthetic substrates containing single psoralen adducts. J Biol Chem. 1988 Nov 15;263(32):16553–16560. [PubMed] [Google Scholar]
  23. Van Houten B., Gamper H., Sancar A., Hearst J. E. DNase I footprint of ABC excinuclease. J Biol Chem. 1987 Sep 25;262(27):13180–13187. [PubMed] [Google Scholar]

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