Molecular mechanisms of DNA repair inhibition by caffeine.
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.
Selby
C P
CP
Department of Biochemistry, University of North Carolina School of Medicine, Chapel Hill 27599.
Sancar
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D002110:Caffeine / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004278:DNA, Superhelical / Q000187:drug effects / Q000528:radiation effects; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000378:metabolism; D003850:Deoxyribonuclease I; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D007700:Kinetics; D011485:Protein Binding; D014466:Ultraviolet Rays
D004278:DNA, Superhelical; D029968:Escherichia coli Proteins; D002110:Caffeine; D004706:Endodeoxyribonucleases; D003850:Deoxyribonuclease I; C036385:endodeoxyribonuclease uvrABC; D004255:Deoxyribodipyrimidine Photo-Lyase