Substrate specificities and excision kinetics of DNA glycosylases involved in base-excision repair of oxidative DNA damage.
Reactive oxygen-derived species such as free radicals are formed in living cells by normal metabolism and exogenous sources, and cause a variety of types of DNA damage such as base and sugar damage, strand breaks and DNA-protein cross-links. Living organisms possess repair systems that repair DNA damage. Oxidative DNA damage caused by free radicals and other oxidizing agents is mainly repaired by base-excision repair (BER), which involves DNA glycosylases in the first step of the repair process. These enzymes remove modified bases from DNA by hydrolyzing the glycosidic bond between the modified base and the sugar moiety, generating an apurinic/apyrimidinic (AP) site. Some also possess AP lyase activity that subsequently cleaves DNA at AP sites. Many DNA glycosylases have been discovered and isolated, and their reaction mechanisms and substrate specificities have been elucidated. Most of the known products of oxidative damage to DNA are substrates of DNA glycosylases with broad or narrow substrate specificities. Some possess cross-activity and remove both pyrimidine- and purine-derived lesions. Overlapping activities between enzymes also exist. Studies of substrate specificities have been performed using either oligodeoxynucleotides with a single modified base embedded at a specific position or damaged DNA substrates containing a multiplicity of pyrimidine- and purine-derived lesions. This paper reviews the substrate specificities and excision kinetics of DNA glycosylases that have been investigated with the use of gas chromatography/mass spectrometry and DNA substrates with multiple lesions.
Dizdaroglu
Miral
M
Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, MD 20899-8311, USA. miral@nist.gov
D000818:Animals; D002849:Chromatography, Gas; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D005057:Eukaryotic Cells; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D010084:Oxidation-Reduction; D011387:Prokaryotic Cells; D017382:Reactive Oxygen Species / Q000009:adverse effects*; D013379:Substrate Specificity; D014764:Viral Proteins / Q000378:metabolism
D017382:Reactive Oxygen Species; D014764:Viral Proteins; D045647:DNA Glycosylases