Repair of UV Light Induced DNA Lesions: A Comparative Study with Model Compounds

Abstract

DNA photolyases are enzymes that catalyze the light-dependend repair of cis-syn-cyclobutane-thymine dimer UV lesions in a variety of organisms. The basis of the repairreaction is an electron transfer from a reduced and deprotonated flavin cofactor to the dimer unit, which splits spontaneously as its radical anion. A second cofactor, which is either an 8-hydroxy-5-deazaflavin or a methenyl-tetrahydrofolate is required as a photo antenna and ensures efficient light absorption. With the help of model compounds that are able to mimic all crucial steps of the repair reaction, detailed mechanistic insights into the repair reaction could be obtained. It became clear, that the enzyme requires the reduced flavin in its deprotonated form and that the repair reaction proceeds most efficiently in polar media, which is in agreement with the observed highly polar flavin binding pocket. Investigations with flavin- and deazaflavin-containing model compounds confirmed that the deazaflavin functions solely as a photo antenna and allowed to study the dependencies of the antenna function on the protonation state of the 8-hydroxy-5-deazaflavin. The ability to mimic the repair reaction with small model compounds allowed finally the development of flavin cofactor functionalized oligo-peptides. Cofactor peptides with the sequence of the DNA-binding domain of the transcription factor MyoD were shown to be able to repair UV light lesions of DNA within a DNA single strand.